Lipids and Lipoproteins in Atherosclerosis: A Commemorative Issue in Honor of Dr. Vladimir V Tertov

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 36939

Special Issue Editors

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
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Special Issue Information

Dear Colleagues,

We want to dedicate this Special Issue to the memory of Dr. Vladimir V Tertov, whom we lost 20 years ago.

Dr. Vladimir Tertov (1955–2001) was an outstanding Russian scientist and prominent and brilliant researcher. The overriding topic of his lifelong investigative work was the role of altered lipoprotein metabolism in the cellular mechanisms of atherogenesis. He continued to promote the importance of the above with courage and vigor, even though this field was not favored in certain periods. He was known worldwide as a skillful and talented researcher and was involved in many symposia, conferences, and workshops.

We both worked with Dr. Tertov for many years. He was more than colleague, co-worker, and co-author, but also our devoted friend. He died 20 years ago shortly after an advanced stage of his illness was discovered. Being fully aware of the quickly approaching outcome of this condition and true to his entire life, he devoted the remained time to meticulous arrangements for completion and advancement of his professional work and goals.

Vladimir Tertov attended the Moscow State University, Moscow, Russia, receiving a M.Sc. in 1972. He obtained his Ph.D. in 1981. Since 1980, Dr. Tertov was appointed at the Institute of Experimental Cardiology, Russian Cardiology Research Centre, Moscow, first as a researcher, then as a senior researcher, a leading researcher, and finally as the head of laboratory until his terminal illness was discovered.

Dr. Tertov began his research related to atherosclerosis in the 1980s, publishing the first report on his pioneering work on the discovery of modified (desialylated) low density lipoprotein in 1987. Since then, more than 400 of his publications concerned the results of investigations carried out by him and his associates on the intrinsic mechanisms of atherosclerosis development. This topic remains relevant to this day, and many of his publications are cited every year by other researchers and scientists. In all the fields of his endeavor, Dr. Tertov achieved an outstanding national and international reputation.

It is of note that Dr. Tertov, himself not a physician, understood the potential implications of his basic research on human diseases, and several research projects were established with his collaboration in several medical specialties.

Dr. Tertov’s personal attributes commanded much respect. He was a very humble man, true to his beliefs and convictions. He was good-natured and considerate to all and loyal as a friend. He was a devoted Christian who supported his Church, and a life-loving man.

This Special Issue defines lipids in their broadest sense, to include different classes and types of lipids and lipid-containing particles, metabolism of lipids in the cells and tissues, lipid transport, etc. Review and research articles that summarize and investigate the role of lipids in various physiological processes, pathology, and disease are very welcome. In particular, the Special Issue aims to translate the results of basic research into the management of various diseases.

In particular, the Special Issue focuses on atherosclerosis. Extra- and intracellular deposition of lipids, predominantly of cholesteryl esters, in arterial intima is one of the earliest manifestations of atherosclerosis. The formation of lipid laden foam cells is recognized as a trigger in the pathogenesis of atherosclerosis. Low-density lipoprotein (LDL) circulating in human blood is the source of lipids accumulated in arterial cells. However, native LDL is unable to induce lipid accumulation in cells. For accumulation to occur, LDL particles must undergo chemical modification. Among pro-atherogenic modified LDLs detected in blood, such forms as oxidized, small dense, desialylated, and electronegative have been described. Multiple modified LDL has been found in the blood of atherosclerotic patients. This LDL has atherogenic properties, that is, it can cause the accumulation of lipids in arterial cells. Further studies of the role of modified LDL should reveal a fundamental modification of LDL that makes it atherogenic.

Large-scale epidemiological studies firmly established the association between low plasma levels of high-density lipoprotein (HDL) and elevated risk of cardiovascular disease. This relationship is thought to reflect the key biological function of HDL, which involves reserve cholesterol transport from the arterial wall to the liver for further excretion from the body. Factors that impair the activities of HDL strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional.

Establishing the relationship between modified LDL, dysfunctional HDL, and inflammation is extremely important for elucidating the mechanisms of atherogenesis, since both lipidosis and local chronic inflammation are closely associated with atherosclerotic lesion starting from the earliest manifestations and accompanying it at all stages of development.

The purpose of the thematic issue is to collect current knowledge on the role of lipid-related causes of various pathologies. Understanding the causes and characteristics of lipid disorders leading to disease should lead to the emergence of new diagnostic and therapeutic approaches in clinical practice.

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

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Keywords

  • anti-inflammatory action
  • atherosclerosis
  • cholesteryl esters
  • diagnostics
  • disease
  • dysfunctional HDL
  • HDL
  • high-density lipoprotein
  • inflammation
  • LDL
  • lipid-containing particles
  • low-density lipoprotein
  • metabolism
  • modified LDL
  • reserve cholesterol transport
  • anti-inflammatory action
  • inflammation
  • diagnostics
  • native LDL
  • pathology
  • reserve cholesterol transport
  • therapy, transport

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Published Papers (15 papers)

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Editorial

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5 pages, 600 KiB  
Editorial
Lipids and Lipoproteins in Atherosclerosis
by Evgeny Bezsonov, Victoria Khotina, Victor Glanz, Igor Sobenin and Alexander Orekhov
Biomedicines 2023, 11(5), 1424; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11051424 - 11 May 2023
Cited by 2 | Viewed by 1302
Abstract
Atherosclerosis is a chronic inflammatory disease [...] Full article
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Research

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15 pages, 3486 KiB  
Article
Determination of Serum Progranulin in Patients with Untreated Familial Hypercholesterolemia
by Bíborka Nádró, Hajnalka Lőrincz, Lilla Juhász, Anita Szentpéteri, Ferenc Sztanek, Éva Varga, Dénes Páll, György Paragh and Mariann Harangi
Biomedicines 2022, 10(4), 771; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040771 - 25 Mar 2022
Cited by 6 | Viewed by 1823
Abstract
Background: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated LDL-C concentrations and is associated with an increased risk of premature atherosclerosis. Progranulin (PGRN) is a multifunctional protein that is known to have various anti-atherogenic effects. To date, the use of [...] Read more.
Background: Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated LDL-C concentrations and is associated with an increased risk of premature atherosclerosis. Progranulin (PGRN) is a multifunctional protein that is known to have various anti-atherogenic effects. To date, the use of serum PGRN in patients with FH has not been studied. Methods: In total, 81 untreated patients with heterozygous FH (HeFH) and 32 healthy control subjects were included in this study. Serum PGRN, sICAM-1, sVCAM-1, oxLDL and TNFα concentrations were determined by ELISA. Lipoprotein subfractions were detected by Lipoprint. We diagnosed FH using the Dutch Lipid Clinic Network criteria. Results: We could not find a significant difference between the PGRN concentrations of the HeFH patients and controls (37.66 ± 9.75 vs. 38.43 ± 7.74 ng/mL, ns.). We found significant positive correlations between triglyceride, TNFα, sVCAM-1, the ratio of small HDL subfraction and PGRN, while significant negative correlations were found between the ratio of large HDL subfraction and PGRN both in the whole study population and in FH patients. PGRN was predicted by sVCAM-1, logTNFα and the ratio of small HDL subfraction. Conclusions: The strong correlations between HDL subfractions, inflammatory markers and PGRN suggest that PGRN may exert its anti-atherogenic effect in HeFH through the alteration of HDL composition and the amelioration of inflammation rather than through decreasing oxidative stress. Full article
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17 pages, 3052 KiB  
Article
Intermittent Hypoxic-Hyperoxic Exposures Effects in Patients with Metabolic Syndrome: Correction of Cardiovascular and Metabolic Profile
by Afina Bestavashvili, Oleg Glazachev, Alexander Bestavashvili, Alexander Suvorov, Yong Zhang, Xinliang Zhang, Andrey Rozhkov, Natalia Kuznetsova, Chavdar Pavlov, Dmitriy Glushenkov and Philippe Kopylov
Biomedicines 2022, 10(3), 566; https://doi.org/10.3390/biomedicines10030566 - 28 Feb 2022
Cited by 9 | Viewed by 2552
Abstract
The aim of this study was to evaluate efficacy and applicability of the “intermittent hypoxic-hyperoxic exposures at rest” (IHHE) protocol as an adjuvant method for metabolic syndrome (MS) cardiometabolic components. A prospective, single-center, randomized controlled clinical study was conducted on 65 patients with [...] Read more.
The aim of this study was to evaluate efficacy and applicability of the “intermittent hypoxic-hyperoxic exposures at rest” (IHHE) protocol as an adjuvant method for metabolic syndrome (MS) cardiometabolic components. A prospective, single-center, randomized controlled clinical study was conducted on 65 patients with MS subject to optimal pharmacotherapy, who were randomly allocated to IHHE or control (CON) groups. The IHHE group completed a 3-week, 5 days/week program of IHHE, each treatment session lasting for 45 min. The CON group followed the same protocol, but was breathing room air through a facial mask instead. The data were collected 2 days before, and at day 2 after the 3-week intervention. As the primary endpoints, systolic (SBP) and diastolic (DBP) blood pressure at rest, as well as arterial stiffness and hepatic tissue elasticity parameters, were selected. After the trial, the IHHE group had a significant decrease in SBP and DBP (Cohen’s d = 1.15 and 0.7, p < 0.001), which became significantly lower (p < 0.001) than in CON. We have failed to detect any pre-post IHHE changes in the arterial stiffness parameters (judging by the Cohen’s d), but after the intervention, cardio-ankle vascular indexes (RCAVI and LCAVI) were significantly lowered in the IHHE group as compared with the CON. The IHHE group demonstrated a medium effect (0.68; 0.69 and 0.71 Cohen’s d) in pre-post decrease of Total Cholesterol (p = 0.04), LDL (p = 0.03), and Liver Steatosis (p = 0.025). In addition, the IHHE group patients demonstrated a statistically significant decrease in pre-post differences (deltas) of RCAVI, LCAVI, all antropometric indices, NTproBNP, Liver Fibrosis, and Steatosis indices, TC, LDL, ALT, and AST in comparison with CON (p = 0.001). The pre-post shifts in SBP, DBP, and HR were significantly correlated with the reduction degree in arterial stiffness (ΔRCAVI, ΔLCAVI), liver fibrosis and steatosis severity (ΔLFibr, ΔLS), anthropometric parameters, liver enzymes, and lipid metabolism in the IHHE group only. Our results suggested that IHHE is a safe, well-tolerated intervention which could be an effective adjuvant therapy in treatment and secondary prevention of atherosclerosis, obesity, and other components of MS that improve the arterial stiffness lipid profile and liver functional state in MS patients. Full article
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11 pages, 272 KiB  
Article
Synergistic Effects of Inflammation and Atherogenic Dyslipidemia on Subclinical Carotid Atherosclerosis Assessed by Ultrasound in Patients with Familial Hypercholesterolemia and Their Family Members
by Po-Chih Lin, Chung-Yen Chen, Charlene Wu and Ta-Chen Su
Biomedicines 2022, 10(2), 367; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020367 - 02 Feb 2022
Cited by 2 | Viewed by 1428
Abstract
Low-density lipoprotein cholesterol (LDL-C) and total to high-density lipoprotein cholesterol (TC/HDL-C) ratio are both common risk factors for atherosclerotic cardiovascular diseases (ASCVDs). However, whether high-sensitivity C-reactive protein (hsCRP) has synergistic or attenuated effects on atherogenic dyslipidemia remains unclear. We investigated subclinical carotid atherosclerosis [...] Read more.
Low-density lipoprotein cholesterol (LDL-C) and total to high-density lipoprotein cholesterol (TC/HDL-C) ratio are both common risk factors for atherosclerotic cardiovascular diseases (ASCVDs). However, whether high-sensitivity C-reactive protein (hsCRP) has synergistic or attenuated effects on atherogenic dyslipidemia remains unclear. We investigated subclinical carotid atherosclerosis in patients with familial hypercholesterolemia (FH) and their family members. A total of 100 families with 761 participants were prospectively studied. Participants were categorized into four groups according to atherogenic dyslipidemia and inflammatory biomarkers. The group with LDL-C ≥ 160 mg/dL (or TC/HDL-C ratio ≥ 5) combined with hsCRP ≥ 2 mg/L have a thicker carotid intima-media thickness (CIMT) in different common carotid artery (CCA) areas and a higher percentage of high plaque scores compared with other subgroups. Multivariate logistic regression analysis revealed a significantly higher adjusted odds ratio (aOR) for thicker CIMT of 3.56 (95% CI: 1.56–8.16) was noted in those with concurrent LDL-C ≥ 160 mg/dL and hsCRP ≥ 2 mg/L compared with the group with concurrent LDL-C < 160 mg/dL and hsCRP < 2 mg/L. Our results demonstrated that systemic inflammation, in terms of higher hsCRP levels ≥ 2 mg/L, synergistically contributed to atherogenic dyslipidemia of higher LDL-C or a higher TC/HDL-C ratio on subclinical atherosclerosis. Full article
12 pages, 3218 KiB  
Article
Mitochondrial Transplantation Enhances Phagocytic Function and Decreases Lipid Accumulation in Foam Cell Macrophages
by Soraya Játiva, Priscila Calle, Selene Torrico, Ángeles Muñoz, Miriam García, Ivet Martinez, Anna Sola and Georgina Hotter
Biomedicines 2022, 10(2), 329; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020329 - 30 Jan 2022
Cited by 6 | Viewed by 2852
Abstract
Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic [...] Read more.
Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic plaques. Several in vitro and in vivo studies have shown changes in the macrophage phenotype and improved phagocytosis after the acquisition of functional mitochondria. However, the effect of mitochondrial transplantation on promoting phagocytosis and phenotypic changes in lipid-loaded macrophages leading to foam cells has not been studied. We aimed to prove that the transplantation of healthy mitochondria to highly cholesterol-loaded macrophages induces macrophage phagocytosis and reduces the macrophage shift towards foam cells. For this purpose, using a murine macrophage cell line, RAW264.7, we determined if mitochondria transplantation to 7-ketocholesterol (7-KC)-loaded macrophages reduced lipid accumulation and modified their phagocytic function. We evidenced that mitochondrial transplantation to 7-KC-loaded macrophages reestablished phagocytosis and reduced lipid content. In addition, CPT1a expression and anti-inflammatory cytokines were restored after mitochondrial transplantation. We have developed a potential therapeutic approach to restore foam cell functionality. Full article
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39 pages, 5278 KiB  
Article
Comprehensive Statistical and Bioinformatics Analysis in the Deciphering of Putative Mechanisms by Which Lipid-Associated GWAS Loci Contribute to Coronary Artery Disease
by Victor Lazarenko, Mikhail Churilin, Iuliia Azarova, Elena Klyosova, Marina Bykanova, Natalia Ob'edkova, Mikhail Churnosov, Olga Bushueva, Galina Mal, Sergey Povetkin, Stanislav Kononov, Yulia Luneva, Sergey Zhabin, Anna Polonikova, Alina Gavrilenko, Igor Saraev, Maria Solodilova and Alexey Polonikov
Biomedicines 2022, 10(2), 259; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020259 - 25 Jan 2022
Cited by 8 | Viewed by 3347
Abstract
The study was designed to evaluate putative mechanisms by which lipid-associated loci identified by genome-wide association studies (GWAS) are involved in the molecular pathogenesis of coronary artery disease (CAD) using a comprehensive statistical and bioinformatics analysis. A total of 1700 unrelated individuals of [...] Read more.
The study was designed to evaluate putative mechanisms by which lipid-associated loci identified by genome-wide association studies (GWAS) are involved in the molecular pathogenesis of coronary artery disease (CAD) using a comprehensive statistical and bioinformatics analysis. A total of 1700 unrelated individuals of Slavic origin from the Central Russia, including 991 CAD patients and 709 healthy controls were examined. Sixteen lipid-associated GWAS loci were selected from European studies and genotyped using the MassArray-4 system. The polymorphisms were associated with plasma lipids such as total cholesterol (rs12328675, rs4846914, rs55730499, and rs838880), LDL-cholesterol (rs3764261, rs55730499, rs1689800, and rs838880), HDL-cholesterol (rs3764261) as well as carotid intima-media thickness/CIMT (rs12328675, rs11220463, and rs1689800). Polymorphisms such as rs4420638 of APOC1 (p = 0.009), rs55730499 of LPA (p = 0.0007), rs3136441 of F2 (p < 0.0001), and rs6065906 of PLTP (p = 0.002) showed significant associations with the risk of CAD, regardless of sex, age, and body mass index. A majority of the observed associations were successfully replicated in large independent cohorts. Bioinformatics analysis allowed establishing (1) phenotype-specific and shared epistatic gene–gene and gene–smoking interactions contributing to all studied cardiovascular phenotypes; (2) lipid-associated GWAS loci might be allele-specific binding sites for transcription factors from gene regulatory networks controlling multifaceted molecular mechanisms of atherosclerosis. Full article
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13 pages, 759 KiB  
Article
Effects of Alirocumab on Triglyceride Metabolism: A Fat-Tolerance Test and Nuclear Magnetic Resonance Spectroscopy Study
by Thomas Metzner, Deborah R. Leitner, Karin Mellitzer, Andrea Beck, Harald Sourij, Tatjana Stojakovic, Gernot Reishofer, Winfried März, Ulf Landmesser, Hubert Scharnagl, Hermann Toplak and Günther Silbernagel
Biomedicines 2022, 10(1), 193; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010193 - 17 Jan 2022
Cited by 4 | Viewed by 2638
Abstract
Background: PCSK9 antibodies strongly reduce LDL cholesterol. The effects of PCSK9 antibodies on triglyceride metabolism are less pronounced. The present study aimed to investigate in detail the effects of alirocumab on triglycerides, triglyceride-rich lipoproteins, and lipase regulators. Methods: A total of 24 patients [...] Read more.
Background: PCSK9 antibodies strongly reduce LDL cholesterol. The effects of PCSK9 antibodies on triglyceride metabolism are less pronounced. The present study aimed to investigate in detail the effects of alirocumab on triglycerides, triglyceride-rich lipoproteins, and lipase regulators. Methods: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were two visits at the study site: the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. Fat-tolerance tests, nuclear magnetic resonance spectroscopy, and enzyme-linked immunosorbent assays were performed to analyze lipid metabolism. Results: A total of 21 participants underwent the first and second investigation. Among these, two participants only received alirocumab twice and 19 patients completed the trial per protocol. All of them had atherosclerotic vascular disease. There was no significant effect of alirocumab treatment on fasting triglycerides, post-prandial triglycerides, or lipoprotein-lipase regulating proteins. Total, large, and small LDL particle concentrations decreased, while the HDL particle concentration increased (all p < 0.001). Mean total circulating PCSK9 markedly increased in response to alirocumab treatment (p < 0.001). Whereas PCSK9 increased more than three-fold in all 19 compliant patients, it remained unchanged in those two patients with two injections only. Conclusion: Significant effects of alirocumab on triglyceride metabolism were not detectable in the ALIROCKS trial. The total circulating PCSK9 concentration might be a useful biomarker to differentiate non-adherence from non-response to PCSK9 antibodies. Full article
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12 pages, 1135 KiB  
Article
Short-Term Treatment with Alirocumab, Flow-Dependent Dilatation of the Brachial Artery and Use of Magnetic Resonance Diffusion Tensor Imaging to Evaluate Vascular Structure: An Exploratory Pilot Study
by Thomas Metzner, Deborah R. Leitner, Gudrun Dimsity, Felix Gunzer, Peter Opriessnig, Karin Mellitzer, Andrea Beck, Harald Sourij, Tatjana Stojakovic, Hannes Deutschmann, Winfried März, Ulf Landmesser, Marianne Brodmann, Gernot Reishofer, Hubert Scharnagl, Hermann Toplak and Günther Silbernagel
Biomedicines 2022, 10(1), 152; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010152 - 11 Jan 2022
Cited by 5 | Viewed by 1646
Abstract
Background: Short-term effects of alirocumab on vascular function have hardly been investigated. Moreover, there is a scarce of reliable non-invasive methods to evaluate atherosclerotic changes of the vasculature. The ALIROCKS trial was performed to address these issues using standard ultrasound-based procedures and a [...] Read more.
Background: Short-term effects of alirocumab on vascular function have hardly been investigated. Moreover, there is a scarce of reliable non-invasive methods to evaluate atherosclerotic changes of the vasculature. The ALIROCKS trial was performed to address these issues using standard ultrasound-based procedures and a completely novel magnetic resonance-based imaging technique. Methods: A total of 24 patients with an indication for treatment with PCSK9 antibodies were recruited. There were 2 visits to the study site, the first before initiation of treatment with alirocumab and the second after 10 weeks of treatment. The key outcome measures included the change of carotid vessel wall fractional anisotropy, a novel magnetic resonance-based measure of vascular integrity, and the changes of carotid intima-media thickness and flow-dependent dilatation of the brachial artery measured with ultrasound. Results: A total of 19 patients completed the trial, 2 patients stopped treatment, 3 patients did not undergo the second visit due to the COVID pandemic. All of them had atherosclerotic vascular disease. Their mean (standard deviation) LDL-cholesterol concentration was 154 (85) mg/dL at baseline and was reduced by 76 (44) mg/dL in response to alirocumab treatment (p < 0.001, n = 19). P-selectin and vascular endothelial growth factors remained unchanged. Flow-dependent dilatation of the brachial artery (+41%, p = 0.241, n = 18), carotid intima-media thickness (p = 0.914, n = 18), and fractional anisotropy of the carotid artery (p = 0.358, n = 13) also did not significantly change. Conclusion: Despite a nominal amelioration for flow-dependent dilatation, significant effects of short-term treatment with alirocumab on vascular function were not detectable. More work would be needed to evaluate, whether fractional anisotropy may be useful in clinical atherosclerosis research. Full article
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10 pages, 639 KiB  
Article
Inverse Association between High-Density Lipoprotein Cholesterol and Adverse Outcomes among Acute Ischemic Stroke Patients with Diabetes Mellitus
by Guoliang Hu, Yuesong Pan, Mengxing Wang, Xia Meng, Yong Jiang, Zixiao Li, Hao Li, Yongjun Wang and Yilong Wang
Biomedicines 2021, 9(12), 1947; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121947 - 20 Dec 2021
Cited by 4 | Viewed by 2488
Abstract
A low high-density lipoprotein cholesterol (HDL-C) level is an identified risk factor for cardiovascular diseases. However, results on the association between HDL-C levels and adverse outcomes in diabetic status still remain limited and controversial. Herein, we evaluated the association between HDL-C levels and [...] Read more.
A low high-density lipoprotein cholesterol (HDL-C) level is an identified risk factor for cardiovascular diseases. However, results on the association between HDL-C levels and adverse outcomes in diabetic status still remain limited and controversial. Herein, we evaluated the association between HDL-C levels and adverse outcomes among acute ischemic stroke (AIS) patients with diabetes mellitus. The cohort comprised 3824 AIS patients with diabetes mellitus (62.7 ± 10.5 years; 34.2% women) from the Third China National Stroke Registry (n = 15,166). Patients were classified into five groups by quintiles of HDL-C. The outcomes included recurrent stroke and major adverse cardiovascular events (MACEs) within 1 year. The relationship between HDL-C levels and the risk of adverse outcomes was analyzed by Cox proportional hazards models. Patients in the lowest quintile of HDL-C had a higher risk of recurrent stroke (hazard ratio (HR) 1.59, 95% confidence interval (CI), 1.12–2.25) and MACEs (HR 1.53, 95% CI, 1.09–2.15) during 1-year follow-up compared with those in the highest quintile of HDL-C. There were linear associations between HDL-C levels and the risks of both recurrent stroke and MACEs. Low HDL-C levels were associated with higher risks of recurrent stroke and MACEs within 1 year in AIS patients with diabetes mellitus. Full article
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12 pages, 1710 KiB  
Article
Obesity-Associated Metabolic Disturbances Reverse the Antioxidant and Anti-Inflammatory Properties of High-Density Lipoproteins in Microglial Cells
by Elena Grao-Cruces, Maria C. Millan-Linares, Maria E. Martin-Rubio, Rocio Toscano, Sergio Barrientos-Trigo, Beatriz Bermudez and Sergio Montserrat-de la Paz
Biomedicines 2021, 9(11), 1722; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111722 - 19 Nov 2021
Cited by 5 | Viewed by 1877
Abstract
High-density lipoproteins (HDLs) play an important role in reverse cholesterol transport and present antioxidant properties, among others. In the central nervous system (CNS), there are HDLs, where these lipoproteins could influence brain health. Owing to the new evidence of HDL functionality remodeling in [...] Read more.
High-density lipoproteins (HDLs) play an important role in reverse cholesterol transport and present antioxidant properties, among others. In the central nervous system (CNS), there are HDLs, where these lipoproteins could influence brain health. Owing to the new evidence of HDL functionality remodeling in obese patients, and the fact that obesity-associated metabolic disturbances is pro-inflammatory and pro-oxidant, the aim of this study was to investigate if HDL functions are depleted in obese patients and obesity-associated microenvironment. HDLs were isolated from normal-weight healthy (nwHDL) and obese men (obHDL). The oxHDL level was measured by malondialdehyde and 4-hydroxynoneal peroxided products. BV2 microglial cells were exposed to different concentrations of nwHDL and obHDL in different obesity-associated pro-inflammatory microenvironments. Our results showed that hyperleptinemia increased oxHDL levels. In addition, nwHDLs reduced pro-inflammatory cytokines’ release and M1 marker gene expression in BV2 microglial cells. Nevertheless, both nwHDL co-administered with LPS+leptin and obHDL promoted BV2 microglial activation and a higher pro-inflammatory cytokine production, thus confirming that obesity-associated metabolic disturbances reverse the antioxidant and anti-inflammatory properties of HDLs in microglial cells. Full article
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14 pages, 2910 KiB  
Article
Oxidized LDL Increase the Proinflammatory Profile of Human Visceral Adipocytes Produced by Hypoxia
by Concepción Santiago-Fernández, Flores Martín-Reyes, Monica Tome, Carolina Gutierrez-Repiso, Diego Fernandez-Garcia, Luis Ocaña-Wilhelmi, Jose Rivas-Becerra, Franz Tatzber, Edith Pursch, Francisco J. Tinahones, Eduardo García-Fuentes and Lourdes Garrido-Sánchez
Biomedicines 2021, 9(11), 1715; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111715 - 18 Nov 2021
Cited by 9 | Viewed by 1926
Abstract
Background: Little is known about the effects of hypoxia on scavenger receptors (SRs) levels in adipocytes. We analyzed the effect of morbid obesity and hypoxia on SRs and inflammation markers in human visceral adipocytes and whether ox-LDL modify the inflammatory profile produced by [...] Read more.
Background: Little is known about the effects of hypoxia on scavenger receptors (SRs) levels in adipocytes. We analyzed the effect of morbid obesity and hypoxia on SRs and inflammation markers in human visceral adipocytes and whether ox-LDL modify the inflammatory profile produced by hypoxia. Methods: We studied in 17 non-obese and 20 subjects with morbid obesity (MO) the mRNA expression of HIF-1α, SRs (LOX-1, MSR1, CL-P1 and CXCL16), IL6 and TNFα in visceral adipocytes and the effect of hypoxia with or without ox-LDL on visceral in vitro-differentiated adipocytes (VDA). Results: HIF-1α, TNFα, IL6, LOX-1, MSR1 and CXCL16 expression in adipocytes was increased in MO when compared with those in non-obese subjects (p < 0.05). The expression of most of the inflammatory markers and SRs gene correlated with HIF-1α. In VDA, hypoxia increased TNFα, IL6, MSR1, CXCL16 and CL-P1 (p < 0.05) in non-obese subjects, and TNFα, IL6, MSR1 and CXCL16 (p < 0.05) in MO. Silencing HIF-1α prevented the increase of TNFα, IL6, LOX-1, MSR1, CL-P1 and CXCL16 expression (p < 0.05). The combination of hypoxia and ox-LDL produced higher TNFα expression (p = 0.041). Conclusions: Morbid obesity and hypoxia increased SRs and inflammatory markers in visceral adipocytes. In a hypoxic state, ox-LDL increased the proinflammatory response of visceral adipocytes to hypoxia. Full article
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Review

Jump to: Editorial, Research

11 pages, 586 KiB  
Review
Atherosclerosis by Virus Infection—A Short Review
by Seang-Hwan Jung and Kyung-Tae Lee
Biomedicines 2022, 10(10), 2634; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102634 - 19 Oct 2022
Cited by 8 | Viewed by 2810
Abstract
Atherosclerosis manifests by the thickening of artery walls and their narrowed channels through the accumulation of plaque. It is one of the most important indicators of cardiovascular disease. It can be caused by various factors, such as smoking, a high cholesterol diet, hypertension, [...] Read more.
Atherosclerosis manifests by the thickening of artery walls and their narrowed channels through the accumulation of plaque. It is one of the most important indicators of cardiovascular disease. It can be caused by various factors, such as smoking, a high cholesterol diet, hypertension, hyperglycemia, and genetic factors. However, atherosclerosis can also develop due to infection. It has been reported that some bacteria and viruses can cause the development of atherosclerosis. Examples of these viruses are influenza viruses, herpes viruses, hepatitis viruses, or papillomaviruses, which are all prevalent and eminent globally for infecting the population worldwide. Moreover, many patients with coronavirus disease 2019 (COVID-19) showed symptoms of cardiovascular disease. In this review paper, the viruses linked to the development of atherosclerosis are introduced, and their viral characteristics, the mechanisms of the development of atherosclerosis, and the current vaccines and antiviral treatment methods are summarized. Full article
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12 pages, 1444 KiB  
Review
Thirty-Five-Year History of Desialylated Lipoproteins Discovered by Vladimir Tertov
by Victor Glanz, Evgeny E. Bezsonov, Vladislav Soldatov and Alexander N. Orekhov
Biomedicines 2022, 10(5), 1174; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051174 - 19 May 2022
Cited by 6 | Viewed by 1554
Abstract
Atherosclerosis is one of the leading causes of death in developed and developing countries. The atherogenicity phenomenon cannot be separated from the role of modified low-density lipoproteins (LDL) in atherosclerosis development. Among the multiple modifications of LDL, desialylation deserves to be discussed separately, [...] Read more.
Atherosclerosis is one of the leading causes of death in developed and developing countries. The atherogenicity phenomenon cannot be separated from the role of modified low-density lipoproteins (LDL) in atherosclerosis development. Among the multiple modifications of LDL, desialylation deserves to be discussed separately, since its atherogenic effects and contribution to atherogenicity are often underestimated or, simply, forgotten. Vladimir Tertov is linked to the origin of the research related to desialylated lipoproteins, including the association of modified LDL with atherogenicity, autoimmune nature of atherosclerosis, and discovery of sialidase activity in blood plasma. The review will briefly discuss all the above-mentioned information, with a description of the current situation in the research. Full article
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13 pages, 539 KiB  
Review
The “Third Violin” in the Cytoskeleton Orchestra—The Role of Intermediate Filaments in the Endothelial Cell’s Life
by Anton S. Shakhov and Irina B. Alieva
Biomedicines 2022, 10(4), 828; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040828 - 01 Apr 2022
Cited by 3 | Viewed by 2323
Abstract
The endothelium plays an important role in the transcytosis of lipoproteins. According to one of the theories, endothelial injury is a triggering factor for the development of atherosclerosis, and intracellular structures, including components of the endotheliocyte cytoskeleton (microtubules, actin, and intermediate filaments), are [...] Read more.
The endothelium plays an important role in the transcytosis of lipoproteins. According to one of the theories, endothelial injury is a triggering factor for the development of atherosclerosis, and intracellular structures, including components of the endotheliocyte cytoskeleton (microtubules, actin, and intermediate filaments), are involved in its development. In contrast to the proteins of tubulin-based microtubules and actin microfilaments, intermediate filaments are comprised of various tissue-specific protein members. Vimentin, the main protein of endothelial intermediate filaments, is one of the most well-studied of these and belongs to type-III intermediate filaments, commonly found in cells of mesenchymal origin. Vimentin filaments are linked mechanically or by signaling molecules to microfilaments and microtubules by which coordinated cell polarisation and migration are carried out, as well as control over several endotheliocyte functions. Moreover, the soluble vimentin acts as an indicator of the state of the cardiovascular system, and the involvement of vimentin in the development and course of atherosclerosis has been demonstrated. Here we discuss current concepts of the participation of vimentin filaments in the vital activity and functioning of endothelial cells, as well as the role of vimentin in the development of inflammatory processes and atherosclerosis. Full article
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19 pages, 1365 KiB  
Review
Lipid Droplets, Phospholipase A2, Arachidonic Acid, and Atherosclerosis
by Miguel A. Bermúdez, María A. Balboa and Jesús Balsinde
Biomedicines 2021, 9(12), 1891; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121891 - 13 Dec 2021
Cited by 15 | Viewed by 3499
Abstract
Lipid droplets, classically regarded as static storage organelles, are currently considered as dynamic structures involved in key processes of lipid metabolism, cellular homeostasis and signaling. Studies on the inflammatory state of atherosclerotic plaques suggest that circulating monocytes interact with products released by endothelial [...] Read more.
Lipid droplets, classically regarded as static storage organelles, are currently considered as dynamic structures involved in key processes of lipid metabolism, cellular homeostasis and signaling. Studies on the inflammatory state of atherosclerotic plaques suggest that circulating monocytes interact with products released by endothelial cells and may acquire a foamy phenotype before crossing the endothelial barrier and differentiating into macrophages. One such compound released in significant amounts into the bloodstream is arachidonic acid, the common precursor of eicosanoids, and a potent inducer of neutral lipid synthesis and lipid droplet formation in circulating monocytes. Members of the family of phospholipase A2, which hydrolyze the fatty acid present at the sn-2 position of phospholipids, have recently emerged as key controllers of lipid droplet homeostasis, regulating their formation and the availability of fatty acids for lipid mediator production. In this paper we discuss recent findings related to lipid droplet dynamics in immune cells and the ways these organelles are involved in regulating arachidonic acid availability and metabolism in the context of atherosclerosis. Full article
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