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Atherosclerosis: From Molecular Biology to Therapeutic Perspective

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 39661

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Dr. Ida Daniela Perrotta

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Department of Biology, Ecology and Earth Sciences, Centre for Microscopy and Microanalysis (CM2), University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy
Interests: atherosclerosis; vascular smooth muscle cell; inflammation; endothelium; cell senescence; apoptosis; lipid metabolism; oxidative stress; nitric oxide; exosomes; vascular calcification; cytokines; growth factors
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Dear Colleagues,

Although studies on the molecular biology of atherogenesis have become the focus of modern atherosclerosis research, the multifactorial pathogenesis of the disease has not been fully elucidated to date. Atherosclerosis is a fibroproliferative disease that proceeds through a series of pathological events involving the inflammatory and immune systems as well as the different types of cells and matrix proteins of the vascular wall. The disease is accompanied by the subendothelial accumulation of lipids and fibrous connective tissue, the phenotypic modulation of SMCs, and the migration of a group of cells, notably monocytes and T cells, through the vascular endothelium in response to inflammation. Along with the traditional cardiovascular risk factors, many other molecular determinants have a role in the appearance, progression, and complication of the disease. Inflammatory cytokines, growth factors, markers of oxidative stress, cell death signals, and mediators of vascular tone all participate in the inflammatory response of atherosclerosis via multiple intricate pathways. Also, arterial wall calcification is considered a direct marker of atherosclerotic disease, yet its underlying molecular mechanisms remain to be elucidated. Other important contributors to atherosclerosis are the exosomes and their miRNAs whose role and interactions with the microenvironment of the plaque can be exploited therapeutically. This Special Issue on “Atherosclerosis: from Molecular Biology to Therapeutic Perspectives” welcomes original research articles and reviews in the field, with a focus on (but not limited to) the molecular mechanisms mediating vascular inflammation, endothelial dysfunction, SMC biology, immune-metabolic interactions, apoptosis, cell-to-cell communication, lipid metabolism, and vascular cell senescence.

Dr. Ida Daniela Perrotta
Guest Editor

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Keywords

Atherosclerosis
Vascular Smooth Muscle Cell
Inflammation
Endothelium
Cell Senescence
Apoptosis
Lipid Metabolism
Oxidative Stress
Nitric Oxide
Exosomes
Vascular Calcification
Cytokines
Growth Factors

Published Papers (13 papers)

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Editorial

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3 pages, 161 KiB

Open AccessEditorial

Atherosclerosis: From Molecular Biology to Therapeutic Perspective

by Ida Perrotta

Int. J. Mol. Sci. 2022, 23(7), 3444; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073444 - 22 Mar 2022

Cited by 1 | Viewed by 1448

Abstract

Atherosclerosis is a chronic and progressive inflammatory disease of the arteries initiated by the functional and structural alteration of the endothelial layer responsible for promoting the subendothelial retention of modified low-density lipoproteins (LDL), which in turn generate an active proinflammatory state in which environmental factors, such as oxidizing agents, growth factors, cytokines, monocyte-macrophages and smooth muscle cells (SMCs), work in cooperation to promote the formation of plaque [...] Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

Research

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14 pages, 6234 KiB

Open AccessArticle

Acetylsalicylic Acid Reduces Passive Aortic Wall Stiffness and Cardiovascular Remodelling in a Mouse Model of Advanced Atherosclerosis

by Lynn Roth, Miche Rombouts, Dorien M. Schrijvers, Besa Emini Veseli, Wim Martinet and Guido R. Y. De Meyer

Int. J. Mol. Sci. 2022, 23(1), 404; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010404 - 30 Dec 2021

Cited by 3 | Viewed by 1956

Abstract

Acetylsalicylic acid (ASA) is widely used in secondary prevention of cardiovascular (CV) disease, mainly because of its antithrombotic effects. Here, we investigated whether ASA can prevent the progression of vessel wall remodelling, atherosclerosis, and CV complications in apolipoprotein E deficient (ApoE^−/−) mice, a model of stable atherosclerosis, and in ApoE^−/− mice with a mutation in the fibrillin-1 gene (Fbn1^C1039G+/−), which is a model of elastic fibre fragmentation, accompanied by exacerbated unstable atherosclerosis. Female ApoE^−/− and ApoE^−/−Fbn1^C1039G+/− mice were fed a Western diet (WD). At 10 weeks of WD, the mice were randomly divided into four groups, receiving either ASA 5 mg/kg/day in the drinking water (ApoE^−/− (n = 14), ApoE^−/−Fbn1^C1039G+/− (n = 19)) or plain drinking water (ApoE^−/− (n = 15), ApoE^−/−Fbn1^C1039G+/− (n = 21)) for 15 weeks. ApoE^−/−Fbn1^C1039G+/− mice showed an increased neutrophil–lymphocyte ratio (NLR) compared to ApoE^−/− mice, and this effect was normalised by ASA. In the proximal ascending aorta wall, ASA-treated ApoE^−/−Fbn1^C1039G+/− mice showed less p-SMAD2/3 positive nuclei, a lower collagen percentage and an increased elastin/collagen ratio, consistent with the values measured in ApoE^−/− mice. ASA did not affect plaque progression, incidence of myocardial infarction and survival of ApoE^−/−Fbn1^C1039G+/− mice, but systolic blood pressure, cardiac fibrosis and hypertrophy were reduced. In conclusion, ASA normalises the NLR, passive wall stiffness and cardiac remodelling in ApoE^−/−Fbn1^C1039G+/− mice to levels observed in ApoE^−/− mice, indicating additional therapeutic benefits of ASA beyond its classical use. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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17 pages, 2909 KiB

Open AccessArticle

Diminazene Aceturate Stabilizes Atherosclerotic Plaque and Attenuates Hepatic Steatosis in apoE-Knockout Mice by Influencing Macrophages Polarization and Taurine Biosynthesis

by Aneta Stachowicz, Anna Wiśniewska, Katarzyna Kuś, Magdalena Białas, Magdalena Łomnicka, Justyna Totoń-Żurańska, Anna Kiepura, Kamila Stachyra, Maciej Suski, Beata Bujak-Giżycka, Jacek Jawień and Rafał Olszanecki

Int. J. Mol. Sci. 2021, 22(11), 5861; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115861 - 30 May 2021

Cited by 8 | Viewed by 3183

Abstract

Atherosclerosis and nonalcoholic fatty liver disease are leading causes of morbidity and mortality in the Western countries. The renin–angiotensin system (RAS) with its two main opposing effectors, i.e., angiotensin II (Ang II) and Ang-(1–7), is widely recognized as a major regulator of cardiovascular function and body metabolic processes. Angiotensin-converting enzyme 2 (ACE2) by breaking-down Ang II forms Ang-(1–7) and thus favors Ang-(1–7) actions. Therefore, the aim of our study was to comprehensively evaluate the influence of prolonged treatment with ACE2 activator, diminazene aceturate (DIZE) on the development of atherosclerotic lesions and hepatic steatosis in apoE^−/− mice fed a high-fat diet (HFD). We have shown that DIZE stabilized atherosclerotic lesions and attenuated hepatic steatosis in apoE^−/− mice fed an HFD. Such effects were associated with decreased total macrophages content and increased α-smooth muscle actin levels in atherosclerotic plaques. Moreover, DIZE changed polarization of macrophages towards increased amount of anti-inflammatory M2 macrophages in the atherosclerotic lesions. Interestingly, the anti-steatotic action of DIZE in the liver was related to the elevated levels of HDL in the plasma, decreased levels of triglycerides, and increased biosynthesis and concentration of taurine in the liver of apoE^−/− mice. However, exact molecular mechanisms of both anti-atherosclerotic and anti-steatotic actions of DIZE require further investigations. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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15 pages, 5625 KiB

Open AccessArticle

Fatty-Acid-Binding Protein 4 as a Novel Contributor to Mononuclear Cell Activation and Endothelial Cell Dysfunction in Atherosclerosis

by Yen-Wen Wu, Ting-Ting Chang, Chia-Chi Chang and Jaw-Wen Chen

Int. J. Mol. Sci. 2020, 21(23), 9245; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239245 - 03 Dec 2020

Cited by 20 | Viewed by 2718

Abstract

Background—Elevated circulating fatty-acid-binding protein 4 (FABP4) levels may be linked with cardiovascular events. This study aimed to investigate the mechanistic role of FABP4 in atherosclerosis. Methods—We recruited 22 patients with angiographically proven coronary artery disease (CAD) and 40 control subjects. Mononuclear cells (MNCs) and human coronary endothelial cells (HCAECs) were used for in vitro study. Results—Patients with CAD were predominantly male with an enhanced prevalence of hypertension, diabetes, and smoking history. FABP4 concentrations were up-regulated in culture supernatants of MNCs from CAD patients, which were positively correlated with the patients’ age, waist–hip ratio, body mass index, serum creatinine, type 2 diabetes, and the presence of hypertension. The adhesiveness of HCAECs to monocytic cells can be activated by FABP4, which was reversed by an FABP4 antibody. FABP4 blockade attenuated the oxidized low-density lipoprotein (oxLDL)-induced expression of ICAM-1, VCAM-1, and P-selectin. FABP4 impaired the tube formation and migration via the ERK/JNK/STAT-1 signaling pathway. FABP4 suppressed phosphorylation of eNOS and expression of SDF-1 protein, both of which can be reversed by treatment with VEGF. Blockade of FABP4 also improved the oxLDL-impaired cell function. Conclusion—We discovered a novel pathogenic role of FABP4 in MNC activation and endothelial dysfunction in atherosclerosis. FABP4 may be a therapeutic target for modulating atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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18 pages, 2034 KiB

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Co-Culture of Primary Human Coronary Artery and Internal Thoracic Artery Endothelial Cells Results in Mutually Beneficial Paracrine Interactions

by Daria Shishkova, Victoria Markova, Maxim Sinitsky, Anna Tsepokina, Alexey Frolov, Nikita Zagorodnikov, Leo Bogdanov and Anton Kutikhin

Int. J. Mol. Sci. 2020, 21(21), 8032; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218032 - 28 Oct 2020

Cited by 8 | Viewed by 2244

Abstract

Although saphenous veins (SVs) are commonly used as conduits for coronary artery bypass grafting (CABG), internal thoracic artery (ITA) grafts have significantly higher long-term patency. As SVs and ITA endothelial cells (ECs) have a considerable level of heterogeneity, we suggested that synergistic paracrine interactions between CA and ITA ECs (HCAECs and HITAECs, respectively) may explain the increased resistance of ITA grafts and adjacent CAs to atherosclerosis and restenosis. In this study, we measured the gene and protein expression of the molecules responsible for endothelial homeostasis, pro-inflammatory response, and endothelial-to-mesenchymal transition in HCAECs co-cultured with either HITAECs or SV ECs (HSaVECs) for an ascending duration. Upon the co-culture, HCAECs and HITAECs showed augmented expression of endothelial nitric oxide synthase (eNOS) and reduced expression of endothelial-to-mesenchymal transition transcription factors Snail and Slug when compared to the HCAEC–HSaVEC model. HCAECs co-cultured with HITAECs demonstrated an upregulation of HES1, a master regulator of arterial specification, of which the expression was also exclusively induced in HSaVECs co-cultured with HCAECs, suggestive of their arterialisation. In addition, co-culture of HCAECs and HITAECs promoted the release of pro-angiogenic molecules. To conclude, co-culture of HCAECs and HITAECs results in reciprocal and beneficial paracrine interactions that might contribute to the better performance of ITA grafts upon CABG. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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16 pages, 2837 KiB

Open AccessArticle

Anti-Apolipoprotein A-1 IgG Influences Neutrophil Extracellular Trap Content at Distinct Regions of Human Carotid Plaques

by Rafaela F. da Silva, Daniela Baptista, Aline Roth, Kapka Miteva, Fabienne Burger, Nicolas Vuilleumier, Federico Carbone, Fabrizio Montecucco, François Mach and Karim J. Brandt

Int. J. Mol. Sci. 2020, 21(20), 7721; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207721 - 19 Oct 2020

Cited by 7 | Viewed by 1955

Abstract

Background: Neutrophils accumulate in atherosclerotic plaques. Neutrophil extracellular traps (NET) were recently identified in experimental atherosclerosis and in complex human lesions. However, not much is known about the NET marker citrullinated histone-3 (H3Cit) expression and functionality in human carotid plaques. Moreover, the association between the proatherosclerotic autoantibody anti-apolipoprotein A-1 (anti-ApoA-1 IgG) and NET has never been investigated. Methods: Atherosclerotic plaques have been obtained from 36 patients with severe carotid stenosis that underwent carotid endarterectomy for severe carotid stenosis. Samples were sectioned into upstream and downstream regions from the same artery segment. Plaque composition and expression of NET markers neutrophil elastase (NE) and H3Cit were quantified by immunohistochemistry. H3Cit expression and function was evaluated by immunofluorescence and confocal analysis in a subset of patients. Results: Pathological features of vulnerable phenotypes were exacerbated in plaques developed at downstream regions, including higher accumulation of neutrophils and enhanced expression of NE and H3Cit, as compared to plaques from upstream regions. The H3Cit signal was also more intense in downstream regions, with significant extracellular distribution in spaces outside of neutrophils. The percentage of H3Cit colocalization with CD66b (neutrophils) was markedly lower in downstream portions of carotid plaques, confirming the extrusion of NET in this region. In agreement, the maximum distance of the H3Cit signal from neutrophils, extrapolated from vortex distance calculation in all possible directions, was also higher in downstream plaques. The serum anti-ApoA-1index positively correlated with the expression of H3Cit in downstream segments of plaques. Expression of the H3Cit signal outside of neutrophils and H3Cit maximal distance from CD66b-positive cells increased in plaques from serum positive anti-ApoA-1 patients compared with serum negative patients. Conclusion: NET elements are differentially expressed in upstream versus downstream regions of human carotid plaques and may be influenced by circulating levels of anti-ApoA-1 IgG. These findings could warrant the investigation of NET elements as potential markers of vulnerability. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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19 pages, 8281 KiB

Open AccessArticle

CCL4 Inhibition in Atherosclerosis: Effects on Plaque Stability, Endothelial Cell Adhesiveness, and Macrophages Activation

by Ting-Ting Chang, Hsin-Ying Yang, Ching Chen and Jaw-Wen Chen

Int. J. Mol. Sci. 2020, 21(18), 6567; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186567 - 08 Sep 2020

Cited by 24 | Viewed by 3688

Abstract

Atherosclerosis is an arterial inflammatory disease. The circulating level of the C-C chemokine ligand (CCL4) is increased in atherosclerotic patients. This study aimed to investigate whether CCL4 inhibition could retard the progression of atherosclerosis. In ApoE knockout mice, CCL4 antibody treatment reduced circulating interleukin-6 (IL-6) and tumor necrosis factor (TNF)-α levels and improved lipid profiles accompanied with upregulation of the liver X receptor. CCL4 inhibition reduced the atheroma areas and modified the progression of atheroma plaques, which consisted of a thicker fibrous cap with a reduced macrophage content and lower matrix metalloproteinase-2 and -9 expressions, suggesting the stabilization of atheroma plaques. Human coronary endothelial cells (HCAECs) and macrophages were stimulated with TNF-α or oxidized LDL (ox-LDL). The induced expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) were attenuated by the CCL4 antibody or CCL4 si-RNA. CCL4 inhibition reduced the adhesiveness of HCAECs, which is an early sign of atherogenesis. CCL4 blockade reduced the activity of metalloproteinase-2 and -9 and the production of TNF-α and IL-6 in stimulated macrophages. The effects of CCL4 inhibition on down-regulating adhesion and inflammation proteins were obtained through the nuclear factor kappa B (NFκB) signaling pathway. The direct inhibition of CCL4 stabilized atheroma and reduced endothelial and macrophage activation. CCL4 may be a novel therapeutic target for modulating atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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Review

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13 pages, 2672 KiB

Open AccessReview

The Initial Human Atherosclerotic Lesion and Lipoprotein Modification—A Deep Connection

by Michael Torzewski

Int. J. Mol. Sci. 2021, 22(21), 11488; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111488 - 25 Oct 2021

Cited by 17 | Viewed by 2651

Abstract

Atherosclerosis research typically focuses on the evolution of intermediate or advanced atherosclerotic lesions rather than on prelesional stages of atherogenesis. Yet these early events may provide decisive leads on the triggers of the pathologic process, before lesions become clinically overt. Thereby, it is mandatory to consider extracellular lipoprotein deposition at this stage as the prerequisite of foam cell formation leading to a remarkable accumulation of LDL (Low Density Lipoproteins). As progression of atherosclerosis displays the characteristic features of a chronic inflammatory process on the one hand and native LDL lacks inflammatory properties on the other hand, the lipoprotein must undergo biochemical modification to become atherogenic. During the last 25 years, evidence was accumulated in support of a different concept on atherogenesis proposing that modification of native LDL occurs through the action of ubiquitous hydrolytic enzymes (enzymatically modified LDL or eLDL) rather than oxidation and contending that the physiological events leading to macrophage uptake and reverse transport of eLDL first occur without inflammation (initiation with reversion). Preventing or reversing initial atherosclerotic lesions would avoid the later stages and therefore prevent clinical manifestations. This concept is in accordance with the response to retention hypothesis directly supporting the strategy of lowering plasma levels of atherogenic lipoproteins as the most successful therapy for atherosclerosis and its sequelae. Apart from but unquestionable closely related to this concept, there are several other hypotheses on atherosclerotic lesion initiation favoring an initiating role of the immune system (‘vascular-associated lymphoid tissue’ (VALT)), defining foam cell formation as a variant of lysosomal storage disease, relating to the concept of the inflammasome with crystalline cholesterol and/or mitochondrial DAMPs (damage-associated molecular patterns) being mandatory in driving arterial inflammation and, last but not least, pointing to miRNAs (micro RNAs) as pivotal players. However, direct anti-inflammatory therapies may prove successful as adjuvant components but will likely never be used in the absence of strategies to lower plasma levels of atherogenic lipoproteins, the key point of the perception that atherosclerosis is not simply an inevitable result of senescence. In particular, given the importance of chemical modifications for lipoprotein atherogenicity, regulation of the enzymes involved might be a tempting target for pharmacological research. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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20 pages, 853 KiB

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Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression

by Krzysztof Laudanski

Int. J. Mol. Sci. 2021, 22(19), 10517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910517 - 29 Sep 2021

Cited by 7 | Viewed by 2699

Abstract

(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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21 pages, 3790 KiB

Open AccessReview

Tryptophan: From Diet to Cardiovascular Diseases

by Nada Joe Melhem and Soraya Taleb

Int. J. Mol. Sci. 2021, 22(18), 9904; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189904 - 14 Sep 2021

Cited by 23 | Viewed by 4974

Abstract

Cardiovascular disease (CVD) is one of the major causes of mortality worldwide. Inflammation is the underlying common mechanism involved in CVD. It has been recently related to amino acid metabolism, which acts as a critical regulator of innate and adaptive immune responses. Among different metabolites that have emerged as important regulators of immune and inflammatory responses, tryptophan (Trp) metabolites have been shown to play a pivotal role in CVD. Here, we provide an overview of the fundamental aspects of Trp metabolism and the interplay between the dysregulation of the main actors involved in Trp metabolism such as indoleamine 2, 3-dioxygenase 1 (IDO) and CVD, including atherosclerosis and myocardial infarction. IDO has a prominent and complex role. Its activity, impacting on several biological pathways, complicates our understanding of its function, particularly in CVD, where it is still under debate. The discrepancy of the observed IDO effects could be potentially explained by its specific cell and tissue contribution, encouraging further investigations regarding the role of this enzyme. Thus, improving our understanding of the function of Trp as well as its derived metabolites will help to move one step closer towards tailored therapies aiming to treat CVD. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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17 pages, 1527 KiB

Open AccessReview

Hybrids as NO Donors

by Ioanna-Chrysoula Tsopka and Dimitra Hadjipavlou-Litina

Int. J. Mol. Sci. 2021, 22(18), 9788; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189788 - 10 Sep 2021

Cited by 3 | Viewed by 2392

Abstract

Cinnamic acid and its derivatives have been studied for a variety of biological properties, including anti-inflammatory, antioxidant, anticancer, antihypertensive, and antibacterial. Many hybrids of cinnamic derivatives with other bioactive molecules have been synthesized and evaluated as nitric oxide (NO) donors. Since NO plays a significant role in various biological processes, including vasodilation, inflammation, and neurotransmission, NO donor groups are incorporated into the structures of already-known bioactive molecules to enhance their biological properties. In this review, we present cinnamic hybrids with NO-donating ability useful in the treatment of several diseases. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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21 pages, 387 KiB

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Harnessing the Potential of CRISPR/Cas in Atherosclerosis: Disease Modeling and Therapeutic Applications

by Wei Sheng Siew, Yin Quan Tang, Chee Kei Kong, Bey-Hing Goh, Serena Zacchigna, Kamal Dua, Dinesh Kumar Chellappan, Acharaporn Duangjai, Surasak Saokaew, Pochamana Phisalprapa and Wei Hsum Yap

Int. J. Mol. Sci. 2021, 22(16), 8422; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168422 - 05 Aug 2021

Cited by 7 | Viewed by 4156

Abstract

Atherosclerosis represents one of the major causes of death globally. The high mortality rates and limitations of current therapeutic modalities have urged researchers to explore potential alternative therapies. The clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR/Cas9) system is commonly deployed for investigating the genetic aspects of Atherosclerosis. Besides, advances in CRISPR/Cas system has led to extensive options for researchers to study the pathogenesis of this disease. The recent discovery of Cas9 variants, such as dCas9, Cas9n, and xCas9 have been established for various applications, including single base editing, regulation of gene expression, live-cell imaging, epigenetic modification, and genome landscaping. Meanwhile, other Cas proteins, such as Cas12 and Cas13, are gaining popularity for their applications in nucleic acid detection and single-base DNA/RNA modifications. To date, many studies have utilized the CRISPR/Cas9 system to generate disease models of atherosclerosis and identify potential molecular targets that are associated with atherosclerosis. These studies provided proof-of-concept evidence which have established the feasibility of implementing the CRISPR/Cas system in correcting disease-causing alleles. The CRISPR/Cas system holds great potential to be developed as a targeted treatment for patients who are suffering from atherosclerosis. This review highlights the advances in CRISPR/Cas systems and their applications in establishing pathogenetic and therapeutic role of specific genes in atherosclerosis. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

18 pages, 720 KiB

Open AccessReview

Novel Therapeutical Approaches to Managing Atherosclerotic Risk

by Rosaria Vincenza Giglio, Anca Pantea Stoian, Khalid Al-Rasadi, Maciej Banach, Angelo Maria Patti, Marcello Ciaccio, Ali A. Rizvi and Manfredi Rizzo

Int. J. Mol. Sci. 2021, 22(9), 4633; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094633 - 28 Apr 2021

Cited by 25 | Viewed by 4203

Abstract

Atherosclerosis is a multifactorial vascular disease that leads to inflammation and stiffening of the arteries and decreases their elasticity due to the accumulation of calcium, small dense Low Density Lipoproteins (sdLDL), inflammatory cells, and fibrotic material. A review of studies pertaining to cardiometabolic risk factors, lipids alterations, hypolipidemic agents, nutraceuticals, hypoglycaemic drugs, atherosclerosis, endothelial dysfunction, and inflammation was performed. There are several therapeutic strategies including Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) inhibitors, inclisiran, bempedoic acid, Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RAs), and nutraceuticals that promise improvement in the atheromatous plaque from a molecular point of view, because have actions on the exposure of the LDL-Receptor (LDL-R), on endothelial dysfunction, activation of macrophages, on lipid oxidation, formations on foam cells, and deposition extracellular lipids. Atheroma plaque reduction both as a result of LDL-Cholesterol (LDL-C) intensive lowering and reducing inflammation and other residual risk factors is an integral part of the management of atherosclerotic disease, and the use of valid therapeutic alternatives appear to be appealing avenues to solving the problem. Full article

(This article belongs to the Special Issue Atherosclerosis: From Molecular Biology to Therapeutic Perspective)

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