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Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology
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Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (29 June 2019) | Viewed by 121726

Special Issue Editors

Prof. Dr. Alexander N. Orekhov

E-Mail Website
Guest Editor
1. Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, 125315 Moscow, Russia
2. Laboratory of Infection Pathology and Molecular Microecology, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia
Interests: atherosclerosis; mitophagy; atherogenicity; autoantibodies; inflammation; innate immunity; cell test; macrophage; membrane transport; modified low density lipoprotein; monocyte; transcriptome; trans-sialydase; enzymatic test; cytokine; epigenetics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Igor A. Sobenin

E-Mail Website
Guest Editor
Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, Moscow, Russia
Interests: atherosclerosis; atherogenesis; cellular and molecular mechanisms; pathogenetic prevention; pathogenetic treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the past two decades, great progress has been achieved in the reduction of cardiovascular mortality. This has been mainly due to the successes of cardiovascular surgery and improvements in lifestyle. Moreover, these achievements have even led some to declare that the battle against atherosclerotic disease has been won; the switching of global research interests to cancer as the most threatening challenge clearly elucidates this tendency.

However, the loss of leading positions of cardiovascular diseases in the structure of total mortality is characteristic only for several developed countries. From a global perspective, atherosclerosis and related diseases remain the leading killers. As for the patients, who gained additional years of life due to surgery and lipid-lowering medications, have they got rid of atherosclerosis? Did the precise cellular and molecular mechanisms of atherogenesis become clear? Was there progress in the development of cardinally new pathogenetic strategies in the development of anti-atherosclerotic treatment? No, there was not. So, it is a proper time to start a new discussion on novel, possibly extraordinary, and disputable ways to defeat atherosclerosis.

The latest achievements in the molecular and cellular biology of atherosclerosis give the hope that novel approaches to diagnostics, prevention, and treatment can be established. The introduction of novel research strategies, like NGS, GWAS, and systems biology, atop of conventional research approaches, may provide the translation of “big data” to general, even theoretical, but plausible solutions for the prevention and treatment of atherosclerotic disease.

Hereby, we invite colleagues to contribute to the present Special Issue with a variety of topics related to recent findings in molecular and cellular pathways of atherosclerosis-related diseases. The papers (both the reviews and original studies) on atherosclerosis and atherogenesis, coronary heart disease, stroke, peripheral atherosclerosis, cerebrovascular insufficiency, arterial hypertension, diabetes mellitus, metabolic syndrome, neurodegenerative diseases, etc., are expected. Comprehensive reviews from the experts in the field are highly welcome as well. We will be glad if contradictory views are also submitted, thus leading to further discussion and polemics.

Prof. Alexander N. Orekhov
Prof. Igor A. Sobenin
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Atherosclerosis
  • atherogenesis
  • coronary heart disease
  • stroke
  • arterial hypertension
  • metabolic syndrome
  • diabetes mellitus
  • lipoprotein metabolism
  • molecular mechanisms
  • cellular mechanisms
  • genetic markers.

Published Papers (25 papers)

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20 pages, 4486 KiB  
Article
Oxidized LDL Modify the Human Adipocyte Phenotype to an Insulin Resistant, Proinflamatory and Proapoptotic Profile
by Concepción Santiago-Fernández, Flores Martin-Reyes, Mónica Tome, Luis Ocaña-Wilhelmi, Jose Rivas-Becerra, Franz Tatzber, Edith Pursch, Francisco J. Tinahones, Eduardo García-Fuentes and Lourdes Garrido-Sánchez
Biomolecules 2020, 10(4), 534; https://0-doi-org.brum.beds.ac.uk/10.3390/biom10040534 - 01 Apr 2020
Cited by 12 | Viewed by 3113
Abstract
Little information exists in humans on the regulation that oxidized low-density lipoprotein (oxLDL) exerts on adipocyte metabolism, which is associated with obesity and type 2 diabetes. The aim was to analyze the oxLDL effects on adipocytokine secretion and scavenger receptors (SRs) and cell [...] Read more.
Little information exists in humans on the regulation that oxidized low-density lipoprotein (oxLDL) exerts on adipocyte metabolism, which is associated with obesity and type 2 diabetes. The aim was to analyze the oxLDL effects on adipocytokine secretion and scavenger receptors (SRs) and cell death markers in human visceral adipocytes. Human differentiated adipocytes from visceral adipose tissue from non-obese and morbidly obese subjects were incubated with increasing oxLDL concentrations. mRNA expression of SRs, markers of apoptosis and autophagy, secretion of adipocytokines, and glucose uptake were analyzed. In non-obese and in morbidly obese subjects, oxLDL produced a decrease in insulin-induced glucose uptake, a significant dose-dependent increase in tumor necrosis factor-α (TNF-α), IL-6, and adiponectin secretion, and a decrease in leptin secretion. OxLDL produced a significant increase of Lox-1 and a decrease in Cxcl16 and Cl-p1 expression. The expression of Bnip3 (marker of apoptosis, necrosis and autophagy) was significantly increased and Bcl2 (antiapoptotic marker) was decreased. OxLDL could sensitize adipocytes to a lower insulin-induced glucose uptake, a more proinflammatory phenotype, and could modify the gene expression involved in apoptosis, autophagy, necrosis, and mitophagy. OxLDL can upregulate Lox-1, and this could lead to a possible amplification of proinflammatory and proapoptotic effects of oxLDL. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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19 pages, 6795 KiB  
Article
LCAT, ApoD, and ApoA1 Expression and Review of Cholesterol Deposition in the Cornea
by Rhonda Flores, Xueting Jin, Janet Chang, Connie Zhang, David G. Cogan, Ernst J. Schaefer and Howard S. Kruth
Biomolecules 2019, 9(12), 785; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120785 - 26 Nov 2019
Cited by 25 | Viewed by 3989
Abstract
Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies plasma cholesterol and increases the capacity of HDL to carry and potentially remove cholesterol from tissues. Cholesterol accumulates within the extracellular [...] Read more.
Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies plasma cholesterol and increases the capacity of HDL to carry and potentially remove cholesterol from tissues. Cholesterol accumulates within the extracellular connective tissue matrix of the cornea stroma in individuals with genetic deficiency of LCAT. LCAT can be activated by apolipoproteins (Apo) including ApoD and ApoA1. ApoA1 also mediates cellular synthesis of HDL. This study examined the expression of LCAT by epithelial cells, keratocytes, and endothelial cells, the cell types that comprise from anterior to posterior the three layers of the cornea. LCAT and ApoD were immunolocalized to all three cell types within the cornea, while ApoA1 was immunolocalized to keratocytes and endothelium but not epithelium. In situ hybridization was used to detect LCAT, ApoD, and ApoA1 mRNA to learn what cell types within the cornea synthesize these proteins. No corneal cells showed mRNA for ApoA1. Keratocytes and endothelium both showed ApoD mRNA, but epithelium did not. Epithelium and endothelium both showed LCAT mRNA, but despite the presence of LCAT protein in keratocytes, keratocytes did not show LCAT mRNA. RNA sequencing analysis of serum-cultured dedifferentiated keratocytes (commonly referred to as corneal stromal fibroblasts) revealed the presence of both LCAT and ApoD (but not ApoA1) mRNA, which was accompanied by their respective proteins detected by immunolabeling of the cultured keratocytes and Western blot analysis of keratocyte lysates. The results indicate that keratocytes in vivo show both ApoA1 and LCAT proteins, but do not synthesize these proteins. Rather, keratocytes in vivo must take up ApoA1 and LCAT from the corneal interstitial tissue fluid. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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24 pages, 3645 KiB  
Article
7-O-Methylpunctatin, a Novel Homoisoflavonoid, Inhibits Phenotypic Switch of Human Arteriolar Smooth Muscle Cells
by Manal Fardoun, Rabah Iratni, Hassan Dehaini, Assaad Eid, Tarek Ghaddar, Tamam El-Elimat, Feras Alali, Adnan Badran, Ali H. Eid and Elias Baydoun
Biomolecules 2019, 9(11), 716; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110716 - 08 Nov 2019
Cited by 11 | Viewed by 4172
Abstract
Remodeling of arterioles is a pivotal event in the manifestation of many inflammation-based cardio-vasculopathologies, such as hypertension. During these remodeling events, vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic phenotype. The latter is characterized by increased proliferation, migration, and [...] Read more.
Remodeling of arterioles is a pivotal event in the manifestation of many inflammation-based cardio-vasculopathologies, such as hypertension. During these remodeling events, vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic phenotype. The latter is characterized by increased proliferation, migration, and invasion. Compounds with anti-inflammatory actions have been successful in attenuating this phenotypic switch. While the vast majority of studies investigating phenotypic modulation were undertaken in VSMCs isolated from large vessels, little is known about the effect of such compounds on phenotypic switch in VSMCs of microvessels (microVSMCs). We have recently characterized a novel homoisoflavonoid that we called 7-O-methylpunctatin (MP). In this study, we show that MP decreased FBS-induced cell proliferation, migration, invasion, and adhesion. MP also attenuated adhesion of THP-1 monocytes to microVSMCs, abolished FBS-induced expression of MMP-2, MMP-9, and NF-κB, as well as reduced activation of ERK1/2 and FAK. Furthermore, MP-treated VSMCs showed an increase in early (myocardin, SM-22α, SM-α) and mid-term (calponin and caldesmon) differentiation markers and a decrease in osteopontin, a protein highly expressed in synthetic VSMCs. MP also reduced transcription of cyclin D1, CDK4 but increased protein levels of p21 and p27. Taken together, these results corroborate an anti-inflammatory action of MP on human microVSMCs. Therefore, by inhibiting the synthetic phenotype of microVSMCs, MP may be a promising modulator for inflammation-induced arteriolar pathophysiology. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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19 pages, 7981 KiB  
Article
Development of a Predictive Model to Induce Atherogenesis and Hepato-Renal Impairment in Female Rats
by Lucas Pires Guarnier, Paulo Vitor Moreira Romão, Rhanany Alan Calloi Palozi, Aniely Oliveira Silva, Bethânia Rosa Lorençone, Aline Aparecida Macedo Marques, Ariany Carvalho dos Santos, Roosevelt Isaias Carvalho Souza, Karine Delgado Souza, Emerson Luiz Botelho Lourenço and Arquimedes Gasparotto Junior
Biomolecules 2019, 9(11), 664; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110664 - 29 Oct 2019
Cited by 9 | Viewed by 2547
Abstract
Therapeutic approaches for the treatment of dyslipidemia and atherosclerosis have radically changed in recent decades. Part of this advance undeniably stems from basic biomedical research that has provided a better understanding and identification of new therapeutic targets. The aim of this work was [...] Read more.
Therapeutic approaches for the treatment of dyslipidemia and atherosclerosis have radically changed in recent decades. Part of this advance undeniably stems from basic biomedical research that has provided a better understanding and identification of new therapeutic targets. The aim of this work was to develop a model to induce atherogenesis and hepato-renal impairment in female Wistar rats. The following groups received the respective treatments for 60 days: control animals, non-ovariectomized rats that received an atherogenic diet (NEAD), ovariectomized rats that received an atherogenic diet (NOAD), non-ovariectomized rats that received an atherogenic diet and oral Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME; LEAD), and ovariectomized rats that received an atherogenic diet and oral l-NAME (LOAD). Animals in the NEAD, NOAD, LEAD, and LOAD groups also received methimazole and cholecalciferol daily. Urinary, biochemical, hemodynamic, and electrocardiographic parameters and renal function were assessed. Samples of the liver, heart, kidney, and arteries were collected to investigate redox status and perform histopathological analyses. All of the groups developed dyslipidemia and hepatic steatosis. Only the NEAD group developed arterial lesions that were compatible with fatty streaks. Renal function was significantly impaired in the LEAD and NOAD groups. These results indicate a viable alternative to induce atherogenesis and hepato-renal impairment in female rats. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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9 pages, 385 KiB  
Article
Creation of Cybrid Cultures Containing mtDNA Mutations m.12315G>A and m.1555G>A, Associated with Atherosclerosis
by Margarita A. Sazonova, Vasily V. Sinyov, Anastasia I. Ryzhkova, Marina D. Sazonova, Zukhra B. Khasanova, Tatiana P. Shkurat, Vasily P. Karagodin, Alexander N. Orekhov and Igor A. Sobenin
Biomolecules 2019, 9(9), 499; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090499 - 18 Sep 2019
Cited by 10 | Viewed by 3477
Abstract
In the present work, a pilot creation of four cybrid cultures with high heteroplasmy level was performed using mitochondrial genome mutations m.12315G>A and m.1555G>A. According to data of our preliminary studies, the threshold heteroplasmy level of mutation m.12315G>A is associated with atherosclerosis. At [...] Read more.
In the present work, a pilot creation of four cybrid cultures with high heteroplasmy level was performed using mitochondrial genome mutations m.12315G>A and m.1555G>A. According to data of our preliminary studies, the threshold heteroplasmy level of mutation m.12315G>A is associated with atherosclerosis. At the same time, for a mutation m.1555G>A, such a heteroplasmy level is associated with the absence of atherosclerosis. Cybrid cultures were created by fusion of rho0-cells and mitochondria from platelets with a high heteroplasmy level of the investigated mutations. To create rho0-cells, THP-1 culture of monocytic origin was taken. According to the results of the study, two cybrid cell lines containing mutation m.12315G>A with the heteroplasmy level above the threshold value (25% and 44%, respectively) were obtained. In addition, two cybrid cell lines containing mutation m.1555G>A with a high heteroplasmy level (24%) were obtained. Cybrid cultures with mtDNA mutation m.12315G>A can be used to model both the occurrence and development of atherosclerosis in cells and the titration of drug therapy for patients with atherosclerosis. With the help of cybrid cultures containing single nucleotide replacement of mitochondrial genome m.1555G>A, it is possible to develop approaches to the gene therapy of atherosclerosis. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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15 pages, 2115 KiB  
Article
Heteroplasmic Variants of Mitochondrial DNA in Atherosclerotic Lesions of Human Aortic Intima
by Igor A. Sobenin, Andrey V. Zhelankin, Zukhra B. Khasanova, Vasily V. Sinyov, Lyudmila V. Medvedeva, Maria O. Sagaidak, Vsevolod J. Makeev, Kira I. Kolmychkova, Anna S. Smirnova, Vasily N. Sukhorukov, Anton Y. Postnov, Andrey V. Grechko and Alexander N. Orekhov
Biomolecules 2019, 9(9), 455; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090455 - 06 Sep 2019
Cited by 11 | Viewed by 3179
Abstract
Mitochondrial dysfunction and oxidative stress are likely involved in atherogenesis. Since the mitochondrial genome variation can alter functional activity of cells, it is necessary to assess the presence in atherosclerotic lesions of mitochondrial DNA (mtDNA) heteroplasmic mutations known to be associated with different [...] Read more.
Mitochondrial dysfunction and oxidative stress are likely involved in atherogenesis. Since the mitochondrial genome variation can alter functional activity of cells, it is necessary to assess the presence in atherosclerotic lesions of mitochondrial DNA (mtDNA) heteroplasmic mutations known to be associated with different pathological processes and ageing. In this study, mtDNA heteroplasmy and copy number (mtCN) were evaluated in the autopsy-derived samples of aortic intima differing by the type of atherosclerotic lesions. To detect mtDNA heteroplasmic variants, next generation sequencing was used, and mtCN measurement was performed by qPCR. It was shown that mtDNA heteroplasmic mutations are characteristic for particular areas of intimal tissue; in 83 intimal samples 55 heteroplasmic variants were found; mean minor allele frequencies level accounted for 0.09, with 12% mean heteroplasmy level. The mtCN variance measured in adjacent areas of intima was high, but atherosclerotic lesions and unaffected intima did not differ significantly in mtCN values. Basing on the ratio of minor and major nucleotide mtDNA variants, we can conclude that there exists the increase in the number of heteroplasmic mtDNA variants, which corresponds to the extent of atherosclerotic morphologic phenotype. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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17 pages, 3030 KiB  
Article
Proinflammatory Action of a New Electronegative Low-Density Lipoprotein Epitope
by Tanize do Espirito Santo Faulin, Soraya Megumi Kazuma, Gustavo Luis Tripodi, Marcela Frota Cavalcante, Felipe Wakasuqui, Cristiano Luis Pinto Oliveira, Maximilia Frazão de Souza Degenhardt, Jussara Michaloski, Ricardo José Giordano, Daniel Francisco Jacon Ketelhuth and Dulcineia Saes Parra Abdalla
Biomolecules 2019, 9(8), 386; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080386 - 20 Aug 2019
Cited by 7 | Viewed by 3186
Abstract
The electronegative low-density lipoprotein, LDL (−), is an endogenously modified LDL subfraction with cytotoxic and proinflammatory actions on endothelial cells, monocytes, and macrophages contributing to the progression of atherosclerosis. In this study, epitopes of LDL (−) were mapped using a phage display library [...] Read more.
The electronegative low-density lipoprotein, LDL (−), is an endogenously modified LDL subfraction with cytotoxic and proinflammatory actions on endothelial cells, monocytes, and macrophages contributing to the progression of atherosclerosis. In this study, epitopes of LDL (−) were mapped using a phage display library of peptides and monoclonal antibodies reactive to this modified lipoprotein. Two different peptide libraries (X6 and CX8C for 6- and 8-amino acid-long peptides, respectively) were used in the mapping. Among all tested peptides, two circular peptides, P1A3 and P2C7, were selected based on their high affinities for the monoclonal antibodies. Small-angle X-ray scattering analysis confirmed their structures as circular rings. P1A3 or P2C7 were quickly internalized by bone marrow-derived murine macrophages as shown by confocal microscopy. P2C7 increased the expression of TNFα, IL-1 β and iNOS as well as the secretion of TNFα, CCL2, and nitric oxide by murine macrophages, similar to the responses induced by LDL (−), although less intense. In contrast, P1A3 did not show pro-inflammatory effects. We identified a mimetic epitope associated with LDL (−), the P2C7 circular peptide, that activates macrophages. Our data suggest that this conformational epitope represents an important danger-associated molecular pattern of LDL (−) that triggers proinflammatory responses. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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17 pages, 1923 KiB  
Article
Genome-Wide Association Study of Metabolic Syndrome Reveals Primary Genetic Variants at CETP Locus in Indians
by Gauri Prasad, Khushdeep Bandesh, Anil K. Giri, Yasmeen Kauser, Prakriti Chanda, Vaisak Parekatt, INDICO, Sandeep Mathur, Sri Venkata Madhu, Pradeep Venkatesh, Anil Bhansali, Raman K. Marwaha, Analabha Basu, Nikhil Tandon and Dwaipayan Bharadwaj
Biomolecules 2019, 9(8), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080321 - 30 Jul 2019
Cited by 15 | Viewed by 3860
Abstract
Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study [...] Read more.
Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6617 MetS and 3476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages—discovery phase (N = 2158) and replication phase (N = 7935). We discovered two variants within/near the CETP gene—rs1800775 and rs3816117—associated with MetS at genome-wide significance level during replication phase in Indians. Additional CETP loci rs7205804, rs1532624, rs3764261, rs247617, and rs173539 also cropped up as modest signals in Indians. Haplotype association analysis revealed GCCCAGC as the strongest haplotype within the CETP locus constituting all seven CETP signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus—rs16890462 in the vicinity of SFRP1 gene. Overlaying gene regulatory data from ENCODE database revealed that single nucleotide polymorphism (SNP) rs16890462 resides in repressive chromatin in human subcutaneous adipose tissue as characterized by the enrichment of H3K27me3 and CTCF marks (repressive gene marks) and diminished H3K36me3 marks (activation gene marks). The variant displayed active DNA methylation marks in adipose tissue, suggesting its likely regulatory activity. Further, the variant also disrupts a potential binding site of a key transcription factor, NRF2, which is known for involvement in obesity and metabolic syndrome. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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14 pages, 2093 KiB  
Article
The Role of Distinctive Sphingolipids in the Inflammatory and Apoptotic Effects of Electronegative LDL on Monocytes
by Núria Puig, Montserrat Estruch, Lei Jin, Jose Luis Sanchez-Quesada and Sonia Benitez
Biomolecules 2019, 9(8), 300; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080300 - 24 Jul 2019
Cited by 14 | Viewed by 3717
Abstract
Electronegative low-density lipoprotein (LDL(−)) is a minor LDL subfraction that is present in blood with inflammatory and apoptotic effects. We aimed to evaluate the role of sphingolipids ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) in the LDL(−)-induced effect on monocytes. Total LDL was [...] Read more.
Electronegative low-density lipoprotein (LDL(−)) is a minor LDL subfraction that is present in blood with inflammatory and apoptotic effects. We aimed to evaluate the role of sphingolipids ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) in the LDL(−)-induced effect on monocytes. Total LDL was subfractioned into native LDL and LDL(−) by anion-exchange chromatography and their sphingolipid content evaluated by mass spectrometry. LDL subfractions were incubated with monocytes in the presence or absence of enzyme inhibitors: chlorpromazine (CPZ), d-erythro-2-(N-myristoyl amino)-1-phenyl-1-propanol (MAPP), and N,N-dimethylsphingosine (DMS), which inhibit Cer, Sph, and S1P generation, respectively. After incubation, we evaluated cytokine release by enzyme-linked immunosorbent assay (ELISA) and apoptosis by flow cytometry. LDL(−) had an increased content in Cer and Sph compared to LDL(+). LDL(−)-induced cytokine release from cultured monocytes was inhibited by CPZ and MAPP, whereas DMS had no effect. LDL(−) promoted monocyte apoptosis, which was inhibited by CPZ, but increased with the addition of DMS. LDL enriched with Sph increased cytokine release in monocytes, and when enriched with Cer, reproduced both the apoptotic and inflammatory effects of LDL(−). These observations indicate that Cer content contributes to the inflammatory and apoptotic effects of LDL(−) on monocytes, whereas Sph plays a more important role in LDL(−)-induced inflammation, and S1P counteracts apoptosis. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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16 pages, 749 KiB  
Article
Antihypertensive Indigenous Lebanese Plants: Ethnopharmacology and a Clinical Trial
by Ali A. Samaha, Mirna Fawaz, Ali Salami, Safaa Baydoun and Ali H. Eid
Biomolecules 2019, 9(7), 292; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070292 - 20 Jul 2019
Cited by 21 | Viewed by 5341
Abstract
Hypertension is highly prevalent among the Lebanese adult population and is indeed the major cause of mortality in Lebanon. Traditional use of antihypertensive medicinal plants has long been practiced. The aim of this study is to document this traditional knowledge and clinically test [...] Read more.
Hypertension is highly prevalent among the Lebanese adult population and is indeed the major cause of mortality in Lebanon. Traditional use of antihypertensive medicinal plants has long been practiced. The aim of this study is to document this traditional knowledge and clinically test the antihypertensive capacity of three of the most commonly used wild plant species Mentha longifolia, Viola odorata and Urtica dioica. Ethno-pharmacological data was collected by personal interviews with herbalists and traditional healers using a semi structured survey questionnaire and assessing relative frequency of citation (RFC). The clinical study was conducted by a randomized, blind, placebo-controlled trial in 29 subjects with mild hypertension distributed in four groups, three plant extract treatments and one placebo. Systolic (SBP) and diastolic blood pressures (DBP) as well as mean arterial blood pressures (MAP) were monitored at weeks 4, 8, 12 and 16 during the treatment with 300 mL/day of plant extract. Results showed that M. longifolia, U. dioica and V. odorata exhibited the highest values of RCF (0.95) followed by Allium ampeloprasum (0.94), Apium graveolens (0.92) and Crataegus azarolus (0.90). The clinical trial revealed dose- and duration-dependent significant reductions in SBP, DBP and MAP of subjects treated with M. longifolia, U. dioica or V. odorata. Our findings indicate that extracts of these plants present an effective, safe and promising potential as a phyto-therapuetical approach for the treatment of mild hypertension. More research on the phytochemistry, pharmacological effects and the underlying mechanisms is necessary. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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9 pages, 400 KiB  
Article
Analysis of Polymorphism rs1333049 (Located at 9P21.3) in the White Population of Western Siberia and Associations with Clinical and Biochemical Markers
by Elena Shakhtshneider, Pavel Orlov, Sergey Semaev, Dinara Ivanoshchuk, Sofia Malyutina, Valery Gafarov, Yuliya Ragino and Mikhail Voevoda
Biomolecules 2019, 9(7), 290; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070290 - 19 Jul 2019
Cited by 6 | Viewed by 2990
Abstract
The 9p21.3 chromosomal region is a marker of the risk of cardiovascular diseases. The aim of this study was to analyze single-nucleotide polymorphism rs1333049 (chr9:22125504) in the population of Western Siberia (Russia) and possible associations with clinical and biochemical parameters. The population included [...] Read more.
The 9p21.3 chromosomal region is a marker of the risk of cardiovascular diseases. The aim of this study was to analyze single-nucleotide polymorphism rs1333049 (chr9:22125504) in the population of Western Siberia (Russia) and possible associations with clinical and biochemical parameters. The population included in the analyses was selected from a sample surveyed within the framework of the Health, Alcohol and Psychosocial Factors In Eastern Europe (HAPIEE) study (9360 participants, >90% white, aged 45–69, males: 50%). In total, 2729 randomly selected patients were included. Plasma lipid levels were determined by standard enzymatic assays. Rs1333049 was analyzed by RT-PCR (BioLabMix, Russia). Frequencies of rs1333049 genotypes C/C (homozygote), C/G (heterozygote), and G/G were 0.22, 0.51, and 0.27 in this population. The Allele G frequency was 0.53. We found an association of allele G with total cholesterol and low-density lipoprotein cholesterol levels among male participants (p = 0.004 and p = 0.002, respectively). Allele C was significantly associated with the risk of myocardial infarction among the male participants (odds ratio 1.96, 95% confidence interval 1.14–3.38, p =  0.017) and the study population (odds ratio 1.83, 95% confidence interval 1.23–2.72, p  =  0.004). Thus, rs1333049 is associated with myocardial infarction in the white population of Western Siberia (Russia). Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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16 pages, 1821 KiB  
Article
Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway
by Adnan Badran, Elias Baydoun, Ali Samaha, Gianfranco Pintus, Joelle Mesmar, Rabah Iratni, Khodr Issa and Ali H. Eid
Biomolecules 2019, 9(6), 227; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060227 - 11 Jun 2019
Cited by 17 | Viewed by 3595
Abstract
Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. Origanum majorana is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, [...] Read more.
Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. Origanum majorana is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, we subjected rat thoracic aortae to increasing doses of an ethanolic extract of Origanum majorana (OME). OME induced relaxation in a dose-dependent manner in endothelium-intact rings. This relaxation was significantly blunted in denuded rings. N(ω)-nitro-l-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) significantly reduced the OME-induced vasorelaxation. Cyclic guanosine monophosphate (cGMP) levels were also increased by OME. Moreover, wortmannin or LY294002 significantly reduced OME-induced vasorelaxation. Blockers of ATP-sensitive or Ca2+-activated potassium channels such as glibenclamide or tetraethylamonium (TEA), respectively, did not significantly affect OME-induced relaxation. Similarly, verapamil, a Ca2+ channel blocker, indomethacin, a non-selective cyclooxygenase inhibitor, and pyrilamine, a H1 histamine receptor blocker, did not significantly modulate the observed relaxation. Taken together, our results show that OME induces vasorelaxation via an endothelium-dependent mechanism involving the phosphoinositide 3-kinase (PI3-K)/ endothelial nitric oxide (NO) synthase (eNOS)/cGMP pathway. Our findings further support the medicinal value of marjoram and provide a basis for its beneficial intake. Although consuming marjoram may have an antihypertensive effect, further studies are needed to better determine its effects in different vascular beds. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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23 pages, 2608 KiB  
Article
Flavin Oxidase-Induced ROS Generation Modulates PKC Biphasic Effect of Resveratrol on Endothelial Cell Survival
by Anna Maria Posadino, Roberta Giordo, Annalisa Cossu, Gheyath K. Nasrallah, Abdullah Shaito, Haissam Abou-Saleh, Ali H. Eid and Gianfranco Pintus
Biomolecules 2019, 9(6), 209; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060209 - 30 May 2019
Cited by 53 | Viewed by 3806
Abstract
Background: Dietary intake of natural antioxidants is thought to impart protection against oxidative-associated cardiovascular diseases. Despite many in vivo studies and clinical trials, this issue has not been conclusively resolved. Resveratrol (RES) is one of the most extensively studied dietary polyphenolic antioxidants. Paradoxically, [...] Read more.
Background: Dietary intake of natural antioxidants is thought to impart protection against oxidative-associated cardiovascular diseases. Despite many in vivo studies and clinical trials, this issue has not been conclusively resolved. Resveratrol (RES) is one of the most extensively studied dietary polyphenolic antioxidants. Paradoxically, we have previously demonstrated that high RES concentrations exert a pro-oxidant effect eventually elevating ROS levels leading to cell death. Here, we further elucidate the molecular determinants underpinning RES-induced oxidative cell death. Methods: Using human umbilical vein endothelial cells (HUVECs), the effect of increasing concentrations of RES on DNA synthesis and apoptosis was studied. In addition, mRNA and protein levels of cell survival or apoptosis genes, as well as protein kinase C (PKC) activity were determined. Results: While high concentrations of RES reduce PKC activity, inhibit DNA synthesis and induce apoptosis, low RES concentrations elicit an opposite effect. This biphasic concentration-dependent effect (BCDE) of RES on PKC activity is mirrored at the molecular level. Indeed, high RES concentrations upregulate the proapoptotic Bax, while downregulating the antiapoptotic Bcl-2, at both mRNA and protein levels. Similarly, high RES concentrations downregulate the cell cycle progression genes, c-myc, ornithine decarboxylase (ODC) and cyclin D1 protein levels, while low RES concentrations display an increasing trend. The BCDE of RES on PKC activity is abrogated by the ROS scavenger Tempol, indicating that this enzyme acts downstream of the RES-elicited ROS signaling. The RES-induced BCDE on HUVEC cell cycle machinery was also blunted by the flavin inhibitor diphenyleneiodonium (DPI), implicating flavin oxidase-generated ROS as the mechanistic link in the cellular response to different RES concentrations. Finally, PKC inhibition abrogates the BCDE elicited by RES on both cell cycle progression and pro-apoptotic gene expression in HUVECs, mechanistically implicating PKC in the cellular response to different RES concentrations. Conclusions: Our results provide new molecular insight into the impact of RES on endothelial function/dysfunction, further confirming that obtaining an optimal benefit of RES is concentration-dependent. Importantly, the BCDE of RES could explain why other studies failed to establish the cardio-protective effects mediated by natural antioxidants, thus providing a guide for future investigation looking at cardio-protection by natural antioxidants. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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12 pages, 1384 KiB  
Article
Inhibiting Extracellular Cathepsin D Reduces Hepatic Steatosis in Sprague–Dawley Rats
by Princy Khurana, Tulasi Yadati, Sandeep Goyal, Atul Dolas, Tom Houben, Yvonne Oligschlaeger, Anil K. Agarwal, Aditya Kulkarni and Ronit Shiri-Sverdlov
Biomolecules 2019, 9(5), 171; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9050171 - 04 May 2019
Cited by 16 | Viewed by 3929
Abstract
Dietary and lifestyle changes are leading to an increased occurrence of non-alcoholic fatty liver disease (NAFLD). Using a hyperlipidemic murine model for non-alcoholic steatohepatitis (NASH), we have previously demonstrated that the lysosomal protease cathepsin D (CTSD) is involved with lipid dysregulation and inflammation. [...] Read more.
Dietary and lifestyle changes are leading to an increased occurrence of non-alcoholic fatty liver disease (NAFLD). Using a hyperlipidemic murine model for non-alcoholic steatohepatitis (NASH), we have previously demonstrated that the lysosomal protease cathepsin D (CTSD) is involved with lipid dysregulation and inflammation. However, despite identifying CTSD as a major player in NAFLD pathogenesis, the specific role of extracellular CTSD in NAFLD has not yet been investigated. Given that inhibition of intracellular CTSD is highly unfavorable due to its fundamental physiological function, we here investigated the impact of a highly specific and potent small-molecule inhibitor of extracellular CTSD (CTD-002) in the context of NAFLD. Treatment of bone marrow-derived macrophages with CTD-002, and incubation of hepatic HepG2 cells with a conditioned medium derived from CTD-002-treated macrophages, resulted in reduced levels of inflammation and improved cholesterol metabolism. Treatment with CTD-002 improved hepatic steatosis in high fat diet-fed rats. Additionally, plasma levels of insulin and hepatic transaminases were significantly reduced upon CTD-002 administration. Collectively, our findings demonstrate for the first time that modulation of extracellular CTSD can serve as a novel therapeutic modality for NAFLD. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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11 pages, 480 KiB  
Article
Matrix Metalloproteinase 9 as a Predictor of Coronary Atherosclerotic Plaque Instability in Stable Coronary Heart Disease Patients with Elevated Lipoprotein(a) Levels
by Marat Ezhov, Maya Safarova, Olga Afanasieva, Maksim Mitroshkin, Yuri Matchin and Sergei Pokrovsky
Biomolecules 2019, 9(4), 129; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9040129 - 29 Mar 2019
Cited by 33 | Viewed by 3633
Abstract
We sought to investigate whether levels of matrix metalloproteinases (MMPs) and their inhibitors predict coronary atherosclerotic plaque instability, as assessed by intravascular ultrasound (IVUS) virtual histology during coronary angiography. Blood samples were collected before angiography in 32 subjects (mean age 56 ± 8 [...] Read more.
We sought to investigate whether levels of matrix metalloproteinases (MMPs) and their inhibitors predict coronary atherosclerotic plaque instability, as assessed by intravascular ultrasound (IVUS) virtual histology during coronary angiography. Blood samples were collected before angiography in 32 subjects (mean age 56 ± 8 years) with stable coronary heart disease (CHD) and elevated lipoprotein(a) (Lp(a), 94 ± 35 mg/dL). Levels of high-sensitivity C-reactive protein (hsCRP), apolipoprotein B100 (apoB100), MMP-7, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 were determined using commercially available enzyme-linked immunosorbent assay kits. Results. The morphology of a total of sixty coronary lesions was assessed by virtual histology IVUS imaging. Eleven (18%) plaques in nine (28%) patients were classified as plaques with an unstable phenotype or a thin-cap fibroatheroma. Age, low-density lipoprotein cholesterol, apoB100, MMP-7, and MMP-9 levels were positively associated with necrotic core volume. Conversely, there was a negative relationship between MMP-7 and -9 levels and fibrous and fibro-fatty tissue volume. Multivariate regression analysis revealed that MMP-9 is a strong independent predictor of atherosclerotic plaque instability in stable CHD patients. In stable CHD patients with elevated Lp(a), MMP-9 levels are positively associated with the size of the necrotic core of coronary atherosclerotic plaques. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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12 pages, 2363 KiB  
Article
Comparison of the Neuroprotective Effects of Aspirin, Atorvastatin, Captopril and Metformin in Diabetes Mellitus
by Maryam Paseban, Reza Mohebbati, Saeed Niazmand, Thozhukat Sathyapalan and Amirhossein Sahebkar
Biomolecules 2019, 9(4), 118; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9040118 - 27 Mar 2019
Cited by 19 | Viewed by 3771
Abstract
Objective: The aim of this study was to investigate the effect of combined intake of a high dose of aspirin, atorvastatin, captopril and metformin on oxidative stress in the brain cortex and hippocampus of streptozotocin (STZ)-induced diabetic rats. Material and methods: Rats were [...] Read more.
Objective: The aim of this study was to investigate the effect of combined intake of a high dose of aspirin, atorvastatin, captopril and metformin on oxidative stress in the brain cortex and hippocampus of streptozotocin (STZ)-induced diabetic rats. Material and methods: Rats were randomly divided into the following 11 groups: control and diabetic (D), as well as 9 groups that were treated with metformin (M, 300 mg/kg) or aspirin (ASA, 120 mg/kg) alone or in different combinations with captopril (C, 50 mg/kg) and/or atorvastatin (AT, 40 mg/kg) as follows: (D + M), (D + ASA), (D + M + ASA), (D + M + C), (D + M + AT), (D + M + C + ASA), (D + M + C + AT), (D + M + AT + ASA) and (D + M + C + AT + ASA). The rats in treatment groups received drugs by gavage daily for six weeks. Serum lipid profile and levels of oxidative markers in the brain cortex and hippocampus tissues were evaluated. Results: The levels of malondialdehyde in the brain cortex and hippocampus in all the treated groups decreased significantly (p < 0.05). There was a significant increase in the total thiol concentration as well as catalase activity in treated rats in (M + AT), (M + C + ASA), (M + C + AT), (M + AT + ASA) and (M + C + AT + ASA) groups in cortex and hippocampus in comparison with the diabetic rats (p < 0.05). Also, the superoxide dismutase activity in all treated rats with medications was significantly increased compared to the diabetic rats (p < 0.05–0.01). Conclusion: Our findings showed that the combined use of high-dose aspirin, metformin, captopril and atorvastatin potentiated their antioxidant effects on the brain, and hence could potentially improve cognitive function with their neuroprotective effects on hippocampus. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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Review

Jump to: Research

15 pages, 568 KiB  
Review
Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes
by Sujuan Ding, Sheng Xu, Yong Ma, Gang Liu, Hongmei Jang and Jun Fang
Biomolecules 2019, 9(12), 850; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120850 - 09 Dec 2019
Cited by 157 | Viewed by 9222
Abstract
The inflammasome is a multiprotein complex that acts to enhance inflammatory responses by promoting the production and secretion of key cytokines. The best-known inflammasome is the NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome. The evidence has shown that the [...] Read more.
The inflammasome is a multiprotein complex that acts to enhance inflammatory responses by promoting the production and secretion of key cytokines. The best-known inflammasome is the NLRP3 (nucleotide-binding oligomerization domain-like receptor [NLR] family pyrin domain-containing 3) inflammasome. The evidence has shown that the NLRP3 inflammasome, IL-1β, thioredoxin-interacting protein (TXNIP), and pyroptosis play vital roles in the development of diabetes. This review summarizes the regulation of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) by NLRP3 via modulation of glucose tolerance, insulin resistance, inflammation, and apoptosis mediated by endoplasmic reticulum stress in adipose tissue. Moreover, NLRP3 participates in intestinal homeostasis and inflammatory conditions, and NLRP3-deficient mice experience intestinal lesions. The diversity of an individual’s gut microbiome and the resultant microbial metabolites determines the extent of their involvement in the physiological and pathological mechanisms within the gut. As such, further study of the interaction between the NLRP3 inflammasome and the complex intestinal environment in disease development is warranted to discover novel therapies for the treatment of diabetes. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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10 pages, 658 KiB  
Review
Lipoprotein(a) as Orchestrator of Calcific Aortic Valve Stenosis
by Johan G. Schnitzler, Lubna Ali, Anouk G. Groenen, Yannick Kaiser and Jeffrey Kroon
Biomolecules 2019, 9(12), 760; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9120760 - 21 Nov 2019
Cited by 25 | Viewed by 4838
Abstract
Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or [...] Read more.
Aortic valve stenosis (AVS) is the most prevalent valvular heart disease in the Western World with exponentially increased incidence with age. If left untreated, the yearly mortality rates increase up to 25%. Currently, no effective pharmacological interventions have been established to treat or prevent AVS. The only treatment modality so far is surgical or transcatheter aortic valve replacement (AVR). Lipoprotein(a) [Lp(a)] has been implicated as a pivotal player in the pathophysiology of calcification of the valves. Patients with elevated levels of Lp(a) have a higher risk of hospitalization or mortality due to the presence of AVS. Multiple studies indicated Lp(a) as a likely causal and independent risk factor for AVS. This review discusses the most important findings and mechanisms related to Lp(a) and AVS in detail. During the progression of AVS, Lp(a) enters the aortic valve tissue at damaged sites of the valves. Subsequently, autotaxin converts lysophosphatidylcholine in lysophosphatidic acid (LysoPA) which in turn acts as a ligand for the LysoPA receptor. This triggers a nuclear factor-κB cascade leading to increased transcripts of interleukin 6, bone morphogenetic protein 2, and runt-related transcription factor 2. This progresses to the actual calcification of the valves through production of alkaline phosphatase and calcium depositions. Furthermore, this review briefly mentions potentially interesting therapies that may play a role in the treatment or prevention of AVS in the near future. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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14 pages, 287 KiB  
Review
Emerging Role of Vitamin D and its Associated Molecules in Pathways Related to Pathogenesis of Thrombosis
by Syed Mohammad, Aastha Mishra and Mohammad Zahid Ashraf
Biomolecules 2019, 9(11), 649; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9110649 - 24 Oct 2019
Cited by 92 | Viewed by 6686
Abstract
Vitamin D, besides having an essential role in calcium and bone metabolism, also acts as a mediator of many non-calcemic effects through modulations of several biological responses. Vitamin D exists in its two major forms, vitamin D2, or commonly known as [...] Read more.
Vitamin D, besides having an essential role in calcium and bone metabolism, also acts as a mediator of many non-calcemic effects through modulations of several biological responses. Vitamin D exists in its two major forms, vitamin D2, or commonly known as ergocalciferol, and vitamin D3, or commonly known as cholecalciferol. Both of these forms bind to vitamin D-binding protein to get transported to all vital target organs, where it serves as a natural ligand to vitamin D receptors for enabling their biological actions. Clinical reports corroborating vitamin D deficiency with an increase in thrombotic episodes implicate the role of vitamin D and its associated molecule in the regulation of thrombosis-related pathways. Thrombosis is the formation and propagation of a blood clot, known as thrombus. It can occur either in the arterial or the venous system resulting in many severe complications, including myocardial infarction, stroke, ischemia, and venous thromboembolism. Vitamin D, directly or indirectly, controls the expression of several genes responsible for the regulation of cellular proliferation, differentiation, apoptosis, and angiogenesis. All of these are the processes of potential relevance to thrombotic disorders. This review, thus, discussed the effects of vitamin D on pathways involved in thrombosis, such as hemostatic process, inflammatory pathway, and endothelial cell activation, with a focus on the molecular mechanisms associated with them. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
14 pages, 636 KiB  
Review
Fibroblasts and Their Pathological Functions in the Fibrosis of Aortic Valve Sclerosis and Atherosclerosis
by Savita Singh and Michael Torzewski
Biomolecules 2019, 9(9), 472; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090472 - 10 Sep 2019
Cited by 40 | Viewed by 9200
Abstract
Cardiovascular diseases, such as atherosclerosis and aortic valve sclerosis (AVS) are driven by inflammation induced by a variety of stimuli, including low-density lipoproteins (LDL), reactive oxygen species (ROS), infections, mechanical stress, and chemical insults. Fibrosis is the process of compensating for tissue injury [...] Read more.
Cardiovascular diseases, such as atherosclerosis and aortic valve sclerosis (AVS) are driven by inflammation induced by a variety of stimuli, including low-density lipoproteins (LDL), reactive oxygen species (ROS), infections, mechanical stress, and chemical insults. Fibrosis is the process of compensating for tissue injury caused by chronic inflammation. Fibrosis is initially beneficial and maintains extracellular homeostasis. However, in the case of AVS and atherosclerosis, persistently active resident fibroblasts, myofibroblasts, and smooth muscle cells (SMCs) perpetually remodel the extracellular matrix under the control of autocrine and paracrine signaling from the immune cells. Myofibroblasts also produce pro-fibrotic factors, such as transforming growth factor-β1 (TGF-β1), angiotensin II (Ang II), and interleukin-1 (IL-1), which allow them to assist in the activation and migration of resident immune cells. Post wound repair, these cells undergo apoptosis or become senescent; however, in the presence of unresolved inflammation and persistence signaling for myofibroblast activation, the tissue homeostasis is disturbed, leading to excessive extracellular matrix (ECM) secretion, disorganized ECM, and thickening of the affected tissue. Accumulating evidence suggests that diverse mechanisms drive fibrosis in cardiovascular pathologies, and it is crucial to understand the impact and contribution of the various mechanisms for the control of fibrosis before the onset of a severe pathological consequence. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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12 pages, 633 KiB  
Review
The Therapeutic Potential of Nanoparticles to Reduce Inflammation in Atherosclerosis
by Armita Mahdavi Gorabi, Nasim Kiaie, Željko Reiner, Federico Carbone, Fabrizio Montecucco and Amirhossein Sahebkar
Biomolecules 2019, 9(9), 416; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9090416 - 26 Aug 2019
Cited by 25 | Viewed by 4551
Abstract
Chronic inflammation is one of the main determinants of atherogenesis. The traditional medications for treatment of atherosclerosis are not very efficient in targeting atherosclerotic inflammation. Most of these drugs are non-selective, anti-inflammatory and immunosuppressive agents that have adverse effects and very limited anti-atherosclerotic [...] Read more.
Chronic inflammation is one of the main determinants of atherogenesis. The traditional medications for treatment of atherosclerosis are not very efficient in targeting atherosclerotic inflammation. Most of these drugs are non-selective, anti-inflammatory and immunosuppressive agents that have adverse effects and very limited anti-atherosclerotic effects, which limits their systemic administration. New approaches using nanoparticles have been investigated to specifically deliver therapeutic agents directly on atherosclerotic lesions. The use of drug delivery systems, such as polymeric nanoparticles, liposomes, and carbon nanotubes are attractive strategies, but some limitations exist. For instance, nanoparticles may alter the drug kinetics, based on the pathophysiological mechanisms of the diseases. In this review, we will update pathophysiological evidence for the use of nanoparticles to reduce inflammation and potentially prevent atherogenesis in different experimental models. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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8 pages, 206 KiB  
Review
Changes in Mitochondrial Genome Associated with Predisposition to Atherosclerosis and Related Disease
by Aleksandrina Volobueva, Andrey Grechko, Shaw-Fang Yet, Igor Sobenin and Alexander Orekhov
Biomolecules 2019, 9(8), 377; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080377 - 18 Aug 2019
Cited by 26 | Viewed by 3259
Abstract
Atherosclerosis-related cardiovascular diseases remain the leading cause of morbidity and mortality, and the search for novel diagnostic and therapeutic methods is ongoing. Mitochondrial DNA (mtDNA) mutations associated with atherosclerosis represent one of the less explored aspects of the disease pathogenesis that may bring [...] Read more.
Atherosclerosis-related cardiovascular diseases remain the leading cause of morbidity and mortality, and the search for novel diagnostic and therapeutic methods is ongoing. Mitochondrial DNA (mtDNA) mutations associated with atherosclerosis represent one of the less explored aspects of the disease pathogenesis that may bring some interesting opportunities for establishing novel molecular markers and, possibly, new points of therapeutic intervention. Recent studies have identified a number of mtDNA mutations, for which the heteroplasmy level was positively or negatively associated with atherosclerosis, including the disease at its early, subclinical stages. In this review, we summarize the results of these studies, providing a list of human mtDNA mutations potentially involved in atherosclerosis. The molecular mechanisms underlying such involvement remain to be elucidated, although it is likely that some of them may be responsible for the increased oxidative stress, which plays an important role in atherosclerosis. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
19 pages, 1045 KiB  
Review
Antioxidants and Atherosclerosis: Mechanistic Aspects
by Khojasteh Malekmohammad, Robert D. E. Sewell and Mahmoud Rafieian-Kopaei
Biomolecules 2019, 9(8), 301; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9080301 - 25 Jul 2019
Cited by 152 | Viewed by 9432
Abstract
Atherosclerosis is a chronic inflammatory disease which is a major cause of coronary heart disease and stroke in humans. It is characterized by intimal plaques and cholesterol accumulation in arterial walls. The side effects of currently prescribed synthetic drugs and their high cost [...] Read more.
Atherosclerosis is a chronic inflammatory disease which is a major cause of coronary heart disease and stroke in humans. It is characterized by intimal plaques and cholesterol accumulation in arterial walls. The side effects of currently prescribed synthetic drugs and their high cost in the treatment of atherosclerosis has prompted the use of alternative herbal medicines, dietary supplements, and antioxidants associated with fewer adverse effects for the treatment of atherosclerosis. This article aims to present the activity mechanisms of antioxidants on atherosclerosis along with a review of the most prevalent medicinal plants employed against this multifactorial disease. The wide-ranging information in this review article was obtained from scientific databases including PubMed, Web of Science, Scopus, Science Direct and Google Scholar. Natural and synthetic antioxidants have a crucial role in the prevention and treatment of atherosclerosis through different mechanisms. These include: The inhibition of low density lipoprotein (LDL) oxidation, the reduction of reactive oxygen species (ROS) generation, the inhibition of cytokine secretion, the prevention of atherosclerotic plaque formation and platelet aggregation, the preclusion of mononuclear cell infiltration, the improvement of endothelial dysfunction and vasodilation, the augmentation of nitric oxide (NO) bioavailability, the modulation of the expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, and the suppression of foam cell formation. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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23 pages, 2809 KiB  
Review
The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance
by Shahenda S. Abdelsalam, Hesham M. Korashy, Asad Zeidan and Abdelali Agouni
Biomolecules 2019, 9(7), 286; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9070286 - 17 Jul 2019
Cited by 72 | Viewed by 9095
Abstract
Endothelial dysfunction is a key feature of cardiovascular disorders associated with obesity and diabetes. Several studies identified protein tyrosine phosphatase (PTP)-1B, a member of the PTP superfamily, as a major negative regulator for insulin receptor signaling and a novel molecular player in endothelial [...] Read more.
Endothelial dysfunction is a key feature of cardiovascular disorders associated with obesity and diabetes. Several studies identified protein tyrosine phosphatase (PTP)-1B, a member of the PTP superfamily, as a major negative regulator for insulin receptor signaling and a novel molecular player in endothelial dysfunction and cardiovascular disease. Unlike other anti-diabetic approaches, genetic deletion or pharmacological inhibition of PTP1B was found to improve glucose homeostasis and insulin signaling without causing lipid buildup in the liver, which represents an advantage over existing therapies. Furthermore, PTP1B was reported to contribute to cardiovascular disturbances, at various molecular levels, which places this enzyme as a unique single therapeutic target for both diabetes and cardiovascular disorders. Synthesizing selective small molecule inhibitors for PTP1B is faced with multiple challenges linked to its similarity of sequence with other PTPs; however, overcoming these challenges would pave the way for novel approaches to treat diabetes and its concurrent cardiovascular complications. In this review article, we summarized the major roles of PTP1B in cardiovascular disease with special emphasis on endothelial dysfunction and its interplay with insulin resistance. Furthermore, we discussed some of the major challenges hindering the synthesis of selective inhibitors for PTP1B. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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23 pages, 2155 KiB  
Review
Promising Directions in Atherosclerosis Treatment Based on Epigenetic Regulation Using MicroRNAs and Long Noncoding RNAs
by Daria Skuratovskaia, Maria Vulf, Aleksandra Komar, Elena Kirienkova and Larisa Litvinova
Biomolecules 2019, 9(6), 226; https://0-doi-org.brum.beds.ac.uk/10.3390/biom9060226 - 11 Jun 2019
Cited by 43 | Viewed by 5878
Abstract
Atherosclerosis is one of the leading causes of mortality from cardiovascular disease (CVD) and is a chronic inflammatory disease of the middle and large arteries caused by a disruption of lipid metabolism. Noncoding RNA (ncRNA), including microRNA (miRNA), small interfering RNA (siRNA) and [...] Read more.
Atherosclerosis is one of the leading causes of mortality from cardiovascular disease (CVD) and is a chronic inflammatory disease of the middle and large arteries caused by a disruption of lipid metabolism. Noncoding RNA (ncRNA), including microRNA (miRNA), small interfering RNA (siRNA) and long noncoding RNA (lncRNA), was investigated for the treatment of atherosclerosis. Regulation of the expression of noncoding RNA targets the constituent element of the pathogenesis of atherosclerosis. Currently, miRNA therapy commonly employs miRNA antagonists and mimic compounds. In this review, attention is focused on approaches to correcting molecular disorders based on the genetic regulation of the transcription of key genes responsible for the development of atherosclerosis. Promising technologies were considered for the treatment of atherosclerosis, and examples are given for technologies that have been shown to be effective in clinical trials. Full article
(This article belongs to the Special Issue Atherosclerosis and Related Diseases: Particular Focus on Molecular Biology)
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