Special Issue "Lipids and Lipoproteins in Health and Disease: Focus on Targeting Atherosclerosis"

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 May 2021).

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; atherosclerosis; 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,

The Special Issue defines lipids in their broadest sense, to include different classes and types of lipids and lipid-containing particles, the metabolism of lipids in 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 basis 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 was 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 an elevated risk of cardiovascular disease. This relationship is thought to reflect the key biological function of HDL, which involves reserving 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. Igor A. Sobenin
Guest Editors

Manuscript Submission Information

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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 (24 papers)

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Research

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Article
The NIH Lipo-COVID Study: A Pilot NMR Investigation of Lipoprotein Subfractions and Other Metabolites in Patients with Severe COVID-19
Biomedicines 2021, 9(9), 1090; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091090 - 26 Aug 2021
Viewed by 645
Abstract
A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to [...] Read more.
A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to their potential utility as prognostic markers. Patients with severe COVID-19 have been reported to have low levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but elevated levels of triglycerides. However, a detailed characterization of the particle counts and sizes of the different plasma lipoproteins in patients with COVID-19 has yet to be reported. In this pilot study, NMR spectroscopy was used to characterize lipoprotein particle numbers and sizes, and various metabolites, in 32 patients with severe COVID-19 admitted to the intensive care unit. Our study revealed markedly reduced HDL particle (HDL-P) numbers at presentation, especially low numbers of small HDL-P (S-HDL-P), and high counts of triglyceride-rich lipoprotein particle (TRL-P), particularly the very small and small TRL subfractions. Moreover, patients with severe COVID-19 were found to have remarkably elevated GlycA levels, and elevated levels of branched-chain amino acids and beta-hydroxybutyrate. Finally, we detected elevated levels of lipoproteins X and Z in most participants, which are distinct markers of hepatic dysfunction, and that was a novel finding. Full article
Article
Expression of miRNAs Targeting ATP Binding Cassette Transporter 1 (ABCA1) among Patients with Significant Carotid Artery Stenosis
Biomedicines 2021, 9(8), 920; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080920 - 30 Jul 2021
Viewed by 451
Abstract
Background: Carotid artery stenosis is a dynamic process associated with an increased risk of cardiovascular events. However, knowledge of biomarkers useful for identifying and quantifying high-risk carotid plaques associated with the increased incidence of cerebrovascular events is insufficient. Therefore, the objectives of this [...] Read more.
Background: Carotid artery stenosis is a dynamic process associated with an increased risk of cardiovascular events. However, knowledge of biomarkers useful for identifying and quantifying high-risk carotid plaques associated with the increased incidence of cerebrovascular events is insufficient. Therefore, the objectives of this study were to evaluate the expression of ATP binding cassette transporter 1 (ABCA1) and validate its target microRNA (miRNA) candidates in human carotid stenosis arteries to identify its potential as a biomarker. Methods: In human carotid stenosis arterial tissues and plasma, the expression of ABCA1 and its target miRNAs (miRNA-33a-5p, 33b-5p, and 148a-3p) were evaluated by quantitative real time-polymerase chain reaction (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA). Results: The expression of ABCA1 was significantly decreased in the plasma of stenosis patients, but its expression was not different in arterial tissues (p < 0.05). However, significantly more target miRNAs were secreted by stenosis patients than normal patients (p < 0.05). Interestingly, lipotoxicity induced by the oleic and palmitic acid (OAPA) or lipopolysaccharide (LPS) treatment of human umbilical vein endothelial cells (HUVECs) dramatically enhanced the gene expression of adipogenic and inflammatory factors, whereas ABCA1 expression was significantly decreased. Conclusions: Therefore, miRNA-33a-5p, 33b-5p, and 148a-3p represent possible biomarkers of carotid artery stenosis by directly targeting ABCA1. Full article
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Article
Relationship between Circulating PCSK9 and Markers of Subclinical Atherosclerosis—The IMPROVE Study
Biomedicines 2021, 9(7), 841; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070841 - 19 Jul 2021
Viewed by 700
Abstract
(1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein [...] Read more.
(1) Background and purpose: circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key regulators of cholesterol metabolism. Despite this, its role as a player in atherosclerosis development is still matter of debate. Here, we investigated the relationships between this protein and several markers of subclinical atherosclerosis. (2) Methods: the IMPROVE study enrolled 3703 European subjects (54–79 years; 48% men; with ≥3 vascular risk factors), asymptomatic for cardiovascular diseases. PCSK9 levels were measured by ELISA. B-mode ultrasound was used to measure markers of carotid subclinical atherosclerosis. (3) Results: in the crude analysis, PCSK9 levels were associated with several baseline measures of carotid intima-media thickness (cIMT) (all p < 0.0001); with cIMT change over time (Fastest-IMTmax-progr) (p = 0.01); with inter-adventitia common carotid artery diameter (ICCAD) (p < 0.0001); and with the echolucency (Grey Scale Median; GSM) of both carotid plaque and plaque-free common carotid IMT (both p < 0.0001). However, after adjustment for age, sex, latitude, and pharmacological treatment, all the afore-mentioned correlations were no longer statistically significant. The lack of correlation was also observed after stratification for sex, latitude, and pharmacological treatments. (4) Conclusions: in subjects who are asymptomatic for cardiovascular diseases, PCSK9 plasma levels do not correlate with vascular damage and/or subclinical atherosclerosis of extracranial carotid arteries. Full article
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Article
Chemically Modified Biomimetic Carbon-Coated Iron Nanoparticles for Stent Coatings: In Vitro Cytocompatibility and In Vivo Structural Changes in Human Atherosclerotic Plaques
Biomedicines 2021, 9(7), 802; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070802 - 12 Jul 2021
Viewed by 686
Abstract
Atherosclerosis, a systematic degenerative disease related to the buildup of plaques in human vessels, remains the major cause of morbidity in the field of cardiovascular health problems, which are the number one cause of death globally. Novel atheroprotective HDL-mimicking chemically modified carbon-coated iron [...] Read more.
Atherosclerosis, a systematic degenerative disease related to the buildup of plaques in human vessels, remains the major cause of morbidity in the field of cardiovascular health problems, which are the number one cause of death globally. Novel atheroprotective HDL-mimicking chemically modified carbon-coated iron nanoparticles ([email protected] NPs) were produced by gas-phase synthesis and modified with organic functional groups of a lipophilic nature. Modified and non-modified [email protected] NPs, immobilized with polycaprolactone on stainless steel, showed high cytocompatibility in human endothelial cell culture. Furthermore, after ex vivo treatment of native atherosclerotic plaques obtained during open carotid endarterectomy surgery, [email protected] NPs penetrated the inner structures and caused structural changes of atherosclerotic plaques, depending on the period of implantation in Wistar rats, serving as a natural bioreactor. The high biocompatibility of the [email protected] NPs shows great potential in the treatment of atherosclerosis disease as an active substance of stent coatings to prevent restenosis and the formation of atherosclerotic plaques. Full article
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Article
Effect of Oxidized Low-Density Lipoprotein on Head and Neck Squamous Cell Carcinomas
Biomedicines 2021, 9(5), 513; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050513 - 05 May 2021
Cited by 1 | Viewed by 684
Abstract
Cardiovascular disease (CVD) and cancer are two major causes of death worldwide. The question is, “Could there be a link between these two pathologies in addition to their shared, common risk factors?” To find some answers, we studied the effect of oxidized low-density [...] Read more.
Cardiovascular disease (CVD) and cancer are two major causes of death worldwide. The question is, “Could there be a link between these two pathologies in addition to their shared, common risk factors?” To find some answers, we studied the effect of oxidized low-density lipoproteins (oxLDL) on head and neck cancer (HNC) cell lines, since oxLDL is a major contributor to atherosclerosis and the principal cause of CVD. In this study, we exposed three HNC cell lines (Detroit 562, UPCI-SCC-131 and FaDu) to oxLDL. We investigated two oxLDL receptors, CD36 and Lox-1, using immunofluorescence. Cancer cell migration was evaluated using Boyden chambers and the Wnt/β-catenin pathway was investigated using Western blotting. We demonstrated that the expression of CD36 and Lox-1 significantly increases after exposure to oxLDL. Moreover, we found that oxLDL reduces the migration of HNC cell lines, an observation that is in line with an increased degradation of β-catenin under oxLDL. Finally, the inhibition of CD36 with sulfosuccinimidyl oleate (SSO) reverses the inhibition of cell migration. In conclusion, we report that oxLDL seems to induce an increase in CD36 expression on HNC cell lines, enhancing the uptake of these lipids in cells to finally decrease cancer cell migration via the CD36/β-catenin pathway. Full article
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Article
The Susceptibility to Diet-Induced Atherosclerosis Is Exacerbated with Aging in C57B1/6 Mice
Biomedicines 2021, 9(5), 487; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050487 - 29 Apr 2021
Viewed by 569
Abstract
The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholesterol transport (RCT). However, it is not clear to what extent this activity is affected by aging or pro-atherogenic conditions. Three and 24-month-old C57Bl/6 mice were fed an atherogenic [...] Read more.
The anti-atherogenic activity of HDL is mainly due to their capacity to mediate reverse cholesterol transport (RCT). However, it is not clear to what extent this activity is affected by aging or pro-atherogenic conditions. Three and 24-month-old C57Bl/6 mice were fed an atherogenic diet (high fat, high cholesterol) for 12 weeks. The aged mice displayed a significant reduction in the capacity of HDL to mediate RCT (29.03%, p < 0.0006). Interestingly, the atherogenic diet significantly stimulated the RCT process in both young and aged mice (241% and 201%, respectively, p < 0.01). However, despite this, significant amounts of cholesterol accumulated in the aortas of mice fed an atherogenic diet as compared to regular chow. The accumulation of cholesterol was more marked in the aortas of aged mice (110% increase, p < 0.002). ABCA1 and ABCG1 protein expression on macrophages decreased significantly (52 to 37% reduction, p < 0.002), whereas their expression on hepatic cells increased significantly (up to 590% for ABCA1 and 116% for ABCG1, p < 0.002). On the other hand, SR-BI protein expression on hepatic cells decreased significantly (42.85%, p < 0.0001). ABCG5, ABCG8, and CYP7a protein expression on hepatic cells was also higher in mice fed an atherogenic diet. The increase was age-dependent for both ABCG5 and ABCG8. Our results suggest that the susceptibility to diet-induced atherosclerosis is exacerbated with aging and is a consequence of the dysregulation of the expression levels of membrane cholesterol transporters. Full article
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Article
Association between Vitamin D Deficiency and High Serum Levels of Small Dense LDL in Middle-Aged Adults
Biomedicines 2021, 9(5), 464; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050464 - 24 Apr 2021
Viewed by 723
Abstract
Recent studies suggested a potential link between vitamin D deficiency and cardiovascular risk factors, including dyslipidemia. This study aimed to investigate the association between serum 25(OH)D levels and atherogenic lipid profiles, specifically, that of small dense low-density lipoprotein-cholesterol (sdLDL-C). From 2009 to 2011, [...] Read more.
Recent studies suggested a potential link between vitamin D deficiency and cardiovascular risk factors, including dyslipidemia. This study aimed to investigate the association between serum 25(OH)D levels and atherogenic lipid profiles, specifically, that of small dense low-density lipoprotein-cholesterol (sdLDL-C). From 2009 to 2011, a total of 715 individuals aged 35–65 without evident cardiovascular disease (CVD) were enrolled. Their levels of serum 25(OH)D and lipid profiles were measured. Vitamin D deficiency was found to be more common in females, smokers, alcohol drinkers, individuals at a younger age, and those who do not exercise regularly. The analysis of lipid profiles revealed that high sdLDL-C levels were associated with low serum vitamin D levels and were more common among cigarette smokers; alcohol drinkers; individuals with hypertension; individuals with high BMI; and those with high levels of fasting blood glucose, triglycerides, LDL-C, and VLDL-C. The use of multivariate logistic regression verified a strong negative correlation between low vitamin D status (serum 25(OH)D < 15 ng/mL) and the three identified biomarkers of atherogenic dyslipidemia: high serum levels of sdLDL-C, triglycerides, and VLDL-C. This study provides strong evidence that vitamin D deficiency is associated with atherogenic dyslipidemia, and in particular, high sdLDL-C levels in middle-aged adults without CVD. Full article
Article
Adipocyte-Specific ACKR3 Regulates Lipid Levels in Adipose Tissue
Biomedicines 2021, 9(4), 394; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040394 - 06 Apr 2021
Cited by 1 | Viewed by 870
Abstract
Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. [...] Read more.
Dysfunctional adipose tissue (AT) may contribute to the pathology of several metabolic diseases through altered lipid metabolism, insulin resistance, and inflammation. Atypical chemokine receptor 3 (ACKR3) expression was shown to increase in AT during obesity, and its ubiquitous elimination caused hyperlipidemia in mice. Although these findings point towards a role of ACKR3 in the regulation of lipid levels, the role of adipocyte-specific ACKR3 has not yet been studied exclusively in this context. In this study, we established adipocyte- and hepatocyte-specific knockouts of Ackr3 in ApoE-deficient mice in order to determine its impact on lipid levels under hyperlipidemic conditions. We show for the first time that adipocyte-specific deletion of Ackr3 results in reduced AT triglyceride and cholesterol content in ApoE-deficient mice, which coincides with increased peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased Angptl4 expression. The role of adipocyte ACKR3 in lipid handling seems to be tissue-specific as hepatocyte ACKR3 deficiency did not demonstrate comparable effects. In summary, adipocyte-specific ACKR3 seems to regulate AT lipid levels in hyperlipidemic Apoe−/− mice, which may therefore be a significant determinant of AT health. Further studies are needed to explore the potential systemic or metabolic effects that adipocyte ACKR3 might have in associated disease models. Full article
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Article
Characterization of Differentially Expressed Circulating miRNAs in Metabolically Healthy versus Unhealthy Obesity
Biomedicines 2021, 9(3), 321; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030321 - 21 Mar 2021
Cited by 1 | Viewed by 1018
Abstract
Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also [...] Read more.
Obese individuals without metabolic comorbidities are categorized as metabolically healthy obese (MHO). MicroRNAs (miRNAs) may be implicated in MHO. This cross-sectional study explores the link between circulating miRNAs and the main components of metabolic syndrome (MetS) in the context of obesity. We also examine oxidative stress biomarkers in MHO vs. metabolically unhealthy obesity (MUO). We analysed 3536 serum miRNAs in 20 middle-aged obese individuals: 10 MHO and 10 MUO. A total of 159 miRNAs were differentially expressed, of which, 72 miRNAs (45.2%) were higher and 87 miRNAs (54.7%) were lower in the MUO group. In addition, miRNAs related to insulin signalling and lipid metabolism pathways were upregulated in the MUO group. Among these miRNAs, hsa-miR-6796-5p and hsa-miR-4697-3p, which regulate oxidative stress, showed significant correlations with glucose, triglycerides, HbA1c and HDLc. Our results provide evidence of a pattern of differentially expressed miRNAs in obesity according to MetS, and identify those related to insulin resistance and lipid metabolism pathways. Full article
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Article
Obesity Affects HDL Metabolism, Composition and Subclass Distribution
Biomedicines 2021, 9(3), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030242 - 27 Feb 2021
Cited by 5 | Viewed by 1374
Abstract
Background: Obesity increases the risk of coronary heart disease, partly due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol levels. Functional impairment of HDL may contribute to the increased cardiovascular mortality, but the effect [...] Read more.
Background: Obesity increases the risk of coronary heart disease, partly due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol levels. Functional impairment of HDL may contribute to the increased cardiovascular mortality, but the effect of obesity on composition, structure, and function of HDL is not well understood. Design and Methods: We determined HDL composition, HDL subclass distribution, parameters of HDL function, and activities of most important enzymes involved in lipoprotein remodeling, including lecithin–cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) in relatively young normal weight (n = 26), overweight (n = 22), and obese (n = 20) women. Results: Obesity (body mass index (BMI) ≥ 30) was associated with noticeable changes in LCAT and CETP activities and altered HDL composition, such as decreased apolipoprotein A-I, cholesterol, and phospholipid content, while pro-inflammatory HDL serum amyloid a content was increased. We observed a marked shift towards smaller HDL subclasses in obesity linked to lower anti-oxidative capacity of serum. LCAT activity, HDL subclass distribution, and HDL-cholesterol were associated with soluble leptin receptor, adiponectin, and liver enzyme activities. Of note, most of these alterations were only seen in obese women but not in overweight women. Conclusions: Obesity markedly affects HDL metabolism, composition, and subclass distribution linked to changes in liver and adipose tissue. HDL dysfunction may contribute to increased cardiovascular risk in obesity. Full article
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Article
Release of Anti-Inflammatory Palmitoleic Acid and Its Positional Isomers by Mouse Peritoneal Macrophages
Biomedicines 2020, 8(11), 480; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8110480 - 06 Nov 2020
Cited by 1 | Viewed by 848
Abstract
Positional isomers of hexadecenoic acid are considered as fatty acids with anti-inflammatory properties. The best known of them, palmitoleic acid (cis-9-hexadecenoic acid, 16:1n-7), has been identified as a lipokine with important beneficial actions in metabolic diseases. Hypogeic acid (cis-7-hexadecenoic acid, 16:1n-9) has been [...] Read more.
Positional isomers of hexadecenoic acid are considered as fatty acids with anti-inflammatory properties. The best known of them, palmitoleic acid (cis-9-hexadecenoic acid, 16:1n-7), has been identified as a lipokine with important beneficial actions in metabolic diseases. Hypogeic acid (cis-7-hexadecenoic acid, 16:1n-9) has been regarded as a possible biomarker of foamy cell formation during atherosclerosis. Notwithstanding the importance of these isomers as possible regulators of inflammatory responses, very little is known about the regulation of their levels and distribution and mobilization among the different lipid pools within the cell. In this work, we describe that the bulk of hexadecenoic fatty acids found in mouse peritoneal macrophages is esterified in a unique phosphatidylcholine species, which contains palmitic acid at the sn-1 position, and hexadecenoic acid at the sn-2 position. This species markedly decreases when the macrophages are activated with inflammatory stimuli, in parallel with net mobilization of free hexadecenoic acid. Using pharmacological inhibitors and specific gene-silencing approaches, we demonstrate that hexadecenoic acids are selectively released by calcium-independent group VIA phospholipase A2 under activation conditions. While most of the released hexadecenoic acid accumulates in free fatty acid form, a significant part is also transferred to other phospholipids to form hexadecenoate-containing inositol phospholipids, which are known to possess growth-factor-like-properties, and are also used to form fatty acid esters of hydroxy fatty acids, compounds with known anti-diabetic and anti-inflammatory properties. Collectively, these data unveil new pathways and mechanisms for the utilization of palmitoleic acid and its isomers during inflammatory conditions, and raise the intriguing possibility that part of the anti-inflammatory activity of these fatty acids may be due to conversion to other lipid mediators. Full article
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Article
Cholesterol Efflux Efficiency of Reconstituted HDL Is Affected by Nanoparticle Lipid Composition
Biomedicines 2020, 8(10), 373; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8100373 - 23 Sep 2020
Cited by 3 | Viewed by 1192
Abstract
Cardiovascular disease (CVD), the leading cause of mortality worldwide is primarily caused by atherosclerosis, which is promoted by the accumulation of low-density lipoproteins into the intima of large arteries. Multiple nanoparticles mimicking natural HDL (rHDL) have been designed to remove cholesterol excess in [...] Read more.
Cardiovascular disease (CVD), the leading cause of mortality worldwide is primarily caused by atherosclerosis, which is promoted by the accumulation of low-density lipoproteins into the intima of large arteries. Multiple nanoparticles mimicking natural HDL (rHDL) have been designed to remove cholesterol excess in CVD therapy. The goal of this investigation was to assess the cholesterol efflux efficiency of rHDLs with different lipid compositions, mimicking different maturation stages of high-density lipoproteins (HDLs) occurring in vivo. Methods: the cholesterol efflux activity of soybean PC (Soy-PC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), DPPC:Chol:1-palmitoyl-2-hydroxy-sn-glycero-3-phosphocholine (LysoPC) and DPPC:18:2 cholesteryl ester (CE):LysoPC rHDLs was determined in several cell models to investigate the contribution of lipid composition to the effectiveness of cholesterol removal. Results: DPPC rHDLs are the most efficient particles, inducing cholesterol efflux in all cellular models and in all conditions the effect was potentiated when the ABCA1 transporter was upregulated. Conclusions: DPPC rHDLs, which resemble nascent HDL, are the most effective particles in inducing cholesterol efflux due to the higher physical binding affinity of cholesterol to the saturated long-chain-length phospholipids and the favored cholesterol transfer from a highly positively curved bilayer, to an accepting planar bilayer such as DPPC rHDLs. The physicochemical characteristics of rHDLs should be taken into consideration to design more efficient nanoparticles to promote cholesterol efflux. Full article
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Review

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Review
Modern Approaches to Lower Lipoprotein(a) Concentrations and Consequences for Cardiovascular Diseases
Biomedicines 2021, 9(9), 1271; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091271 - 20 Sep 2021
Viewed by 971
Abstract
Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could [...] Read more.
Lipoprotein(a) (Lp(a)) is a low density lipoprotein particle that is associated with poor cardiovascular prognosis due to pro-atherogenic, pro-thrombotic, pro-inflammatory and pro-oxidative properties. Traditional lipid-lowering therapy does not provide a sufficient Lp(a) reduction. For PCSK9 inhibitors a small reduction of Lp(a) levels could be shown, which was associated with a reduction in cardiovascular events, independently of the effect on LDL cholesterol. Another option is inclisiran, for which no outcome data are available yet. Lipoprotein apheresis acutely and in the long run decreases Lp(a) levels and effectively improves cardiovascular prognosis in high-risk patients who cannot be satisfactorily treated with drugs. New drugs inhibiting the synthesis of apolipoprotein(a) (an antisense oligonucleotide (Pelacarsen) and two siRNA drugs) are studied. Unlike LDL-cholesterol, for Lp(a) no target value has been defined up to now. This overview presents data of modern capabilities of cardiovascular risk reduction by lowering Lp(a) level. Full article
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Review
Lipids and Lipoproteins in Health and Disease: Focus on Targeting Atherosclerosis
Biomedicines 2021, 9(8), 985; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080985 - 09 Aug 2021
Cited by 2 | Viewed by 699
Abstract
Despite advances in pharmacotherapy, intervention devices and techniques, residual cardiovascular risks still cause a large burden on public health. Whilst most guidelines encourage achieving target levels of specific lipids and lipoproteins to reduce these risks, increasing evidence has shown that molecular modification of [...] Read more.
Despite advances in pharmacotherapy, intervention devices and techniques, residual cardiovascular risks still cause a large burden on public health. Whilst most guidelines encourage achieving target levels of specific lipids and lipoproteins to reduce these risks, increasing evidence has shown that molecular modification of these lipoproteins also has a critical impact on their atherogenicity. Modification of low-density lipoprotein (LDL) by oxidation, glycation, peroxidation, apolipoprotein C-III adhesion, and the small dense subtype largely augment its atherogenicity. Post-translational modification by oxidation, carbamylation, glycation, and imbalance of molecular components can reduce the capacity of high-density lipoprotein (HDL) for reverse cholesterol transport. Elevated levels of triglycerides (TGs), apolipoprotein C-III and lipoprotein(a), and a decreased level of apolipoprotein A-I are closely associated with atherosclerotic cardiovascular disease. Pharmacotherapies aimed at reducing TGs, lipoprotein(a), and apolipoprotein C-III, and enhancing apolipoprotein A-1 are undergoing trials, and promising preliminary results have been reported. In this review, we aim to update the evidence on modifications of major lipid and lipoprotein components, including LDL, HDL, TG, apolipoprotein, and lipoprotein(a). We also discuss examples of translating findings from basic research to potential therapeutic targets for drug development. Full article
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Review
Recognition of Oxidized Lipids by Macrophages and Its Role in Atherosclerosis Development
Biomedicines 2021, 9(8), 915; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9080915 - 29 Jul 2021
Cited by 2 | Viewed by 465
Abstract
Atherosclerosis is a multifactorial chronic disease that has a prominent inflammatory component. Currently, atherosclerosis is regarded as an active autoimmune process that involves both innate and adaptive immune pathways. One of the drivers of this process is the presence of modified low-density lipoprotein [...] Read more.
Atherosclerosis is a multifactorial chronic disease that has a prominent inflammatory component. Currently, atherosclerosis is regarded as an active autoimmune process that involves both innate and adaptive immune pathways. One of the drivers of this process is the presence of modified low-density lipoprotein (LDL). For instance, lipoprotein oxidation leads to the formation of oxidation-specific epitopes (OSE) that can be recognized by the immune cells. Macrophage response to OSEs is recognized as a key trigger for initiation and a stimulator of progression of the inflammatory process in the arteries. At the same time, the role of oxidized LDL components is not limited to pro-inflammatory stimulation, but includes immunoregulatory effects that can have protective functions. It is, therefore, important to better understand the complexity of oxidized LDL effects in atherosclerosis in order to develop new therapeutic approaches to correct the inflammatory and metabolic imbalance associated with this disorder. In this review, we discuss the process of oxidized LDL formation, mechanisms of OSE recognition by macrophages and the role of these processes in atherosclerosis. Full article
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Review
Dyslipidaemia in Type 1 Diabetes: Molecular Mechanisms and Therapeutic Opportunities
Biomedicines 2021, 9(7), 826; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070826 - 16 Jul 2021
Viewed by 681
Abstract
Cardiovascular disease (CVD) is the leading cause of death in Type 1 Diabetes (T1D). The molecular basis for atherosclerosis in T1D is heavily influenced by hyperglycaemia and its atherogenic effects on LDL. Ongoing research into the distinct pathophysiology of atherosclerosis in T1D offers [...] Read more.
Cardiovascular disease (CVD) is the leading cause of death in Type 1 Diabetes (T1D). The molecular basis for atherosclerosis in T1D is heavily influenced by hyperglycaemia and its atherogenic effects on LDL. Ongoing research into the distinct pathophysiology of atherosclerosis in T1D offers exciting opportunities for novel approaches to calculate CVD risk in patients with T1D and to manage this risk appropriately. Currently, despite the increased risk of CVD in the T1D population, there are few tools available for estimating the risk of CVD in younger patients. This poses significant challenges for clinicians in selecting which patients might benefit from lipid-lowering therapies over the long term. The current best practice guidance for the management of dyslipidaemia in T1D is generally based on evidence from patients with T2D and the opinion of experts in the field. In this review article, we explore the unique pathophysiology of atherosclerosis in T1D, with a specific focus on hyperglycaemia-induced damage and atherogenic LDL modifications. We also discuss the current clinical situation of managing these patients across paediatric and adult populations, focusing on the difficulties posed by a lack of strong evidence and various barriers to treatment. Full article
Review
The Importance of Lipoprotein Lipase Regulation in Atherosclerosis
Biomedicines 2021, 9(7), 782; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070782 - 06 Jul 2021
Cited by 1 | Viewed by 925
Abstract
Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein [...] Read more.
Lipoprotein lipase (LPL) plays a major role in the lipid homeostasis mainly by mediating the intravascular lipolysis of triglyceride rich lipoproteins. Impaired LPL activity leads to the accumulation of chylomicrons and very low-density lipoproteins (VLDL) in plasma, resulting in hypertriglyceridemia. While low-density lipoprotein cholesterol (LDL-C) is recognized as a primary risk factor for atherosclerosis, hypertriglyceridemia has been shown to be an independent risk factor for cardiovascular disease (CVD) and a residual risk factor in atherosclerosis development. In this review, we focus on the lipolysis machinery and discuss the potential role of triglycerides, remnant particles, and lipolysis mediators in the onset and progression of atherosclerotic cardiovascular disease (ASCVD). This review details a number of important factors involved in the maturation and transportation of LPL to the capillaries, where the triglycerides are hydrolyzed, generating remnant lipoproteins. Moreover, LPL and other factors involved in intravascular lipolysis are also reported to impact the clearance of remnant lipoproteins from plasma and promote lipoprotein retention in capillaries. Apolipoproteins (Apo) and angiopoietin-like proteins (ANGPTLs) play a crucial role in regulating LPL activity and recent insights into LPL regulation may elucidate new pharmacological means to address the challenge of hypertriglyceridemia in atherosclerosis development. Full article
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Review
SR-B1, a Key Receptor Involved in the Progression of Cardiovascular Disease: A Perspective from Mice and Human Genetic Studies
Biomedicines 2021, 9(6), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060612 - 27 May 2021
Cited by 4 | Viewed by 991
Abstract
High plasma level of low-density lipoprotein (LDL) is the main driver of the initiation and progression of cardiovascular disease (CVD). Nevertheless, high-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein due to its role in reverse cholesterol transport and its ability to receive cholesterol [...] Read more.
High plasma level of low-density lipoprotein (LDL) is the main driver of the initiation and progression of cardiovascular disease (CVD). Nevertheless, high-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein due to its role in reverse cholesterol transport and its ability to receive cholesterol that effluxes from macrophages in the artery wall. The scavenger receptor B class type 1 (SR-B1) was identified as the high-affinity HDL receptor, which facilitates the selective uptake of cholesterol ester (CE) into the liver via HDL and is also implicated in the plasma clearance of LDL, very low-density lipoprotein (VLDL) and lipoprotein(a) (Lp(a)). Thus, SR-B1 is a multifunctional receptor that plays a main role in the metabolism of different lipoproteins. The aim of this review is to highlight the association between SR-B1 and CVD risk through mice and human genetic studies. Full article
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Review
Proatherogenic Sialidases and Desialylated Lipoproteins: 35 Years of Research and Current State from Bench to Bedside
Biomedicines 2021, 9(6), 600; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060600 - 25 May 2021
Cited by 2 | Viewed by 951
Abstract
This review summarizes the main achievements in basic and clinical research of atherosclerosis. Focusing on desialylation as the first and the most important reaction of proatherogenic pathological cascade, we speak of how desialylation increases the atherogenic properties of low density lipoproteins and decreases [...] Read more.
This review summarizes the main achievements in basic and clinical research of atherosclerosis. Focusing on desialylation as the first and the most important reaction of proatherogenic pathological cascade, we speak of how desialylation increases the atherogenic properties of low density lipoproteins and decreases the anti-atherogenic properties of high density lipoproteins. The separate sections of this paper are devoted to immunogenicity of lipoproteins, the enzymes contributing to their desialylation and animal models of atherosclerosis. In addition, we evaluate the available experimental and diagnostic protocols that can be used to develop new therapeutic approaches for atherosclerosis. Full article
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Review
Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins
Biomedicines 2021, 9(6), 587; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060587 - 21 May 2021
Cited by 2 | Viewed by 1086
Abstract
Lipoproteins interact with immune cells, macrophages and endothelial cells - key players of the innate and adaptive immune system. High-density lipoprotein (HDL) particles seem to have evolved as part of the innate immune system since certain HDL subspecies contain combinations of apolipoproteins with [...] Read more.
Lipoproteins interact with immune cells, macrophages and endothelial cells - key players of the innate and adaptive immune system. High-density lipoprotein (HDL) particles seem to have evolved as part of the innate immune system since certain HDL subspecies contain combinations of apolipoproteins with immune regulatory functions. HDL is enriched in anti-inflammatory lipids, such as sphingosine-1-phosphate and certain saturated lysophospholipids. HDL reduces inflammation and protects against infection by modulating immune cell function, vasodilation and endothelial barrier function. HDL suppresses immune cell activation at least in part by modulating the cholesterol content in cholesterol/sphingolipid-rich membrane domains (lipid rafts), which play a critical role in the compartmentalization of signaling pathways. Acute infections, inflammation or autoimmune diseases lower HDL cholesterol levels and significantly alter HDL metabolism, composition and function. Such alterations could have a major impact on disease progression and may affect the risk for infections and cardiovascular disease. This review article aims to provide a comprehensive overview of the immune cell modulatory activities of HDL. We focus on newly discovered activities of HDL-associated apolipoproteins, enzymes, lipids, and HDL mimetic peptides. Full article
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Review
Anti-Atherosclerotic Potential of Free Fatty Acid Receptor 4 (FFAR4)
Biomedicines 2021, 9(5), 467; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050467 - 24 Apr 2021
Cited by 2 | Viewed by 930
Abstract
Fatty acids (FAs) are considered not only as a basic nutrient, but are also recognized as signaling molecules acting on various types of receptors. The receptors activated by FAs include the family of rhodopsin-like receptors: GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), GPR120 (FFAR4), [...] Read more.
Fatty acids (FAs) are considered not only as a basic nutrient, but are also recognized as signaling molecules acting on various types of receptors. The receptors activated by FAs include the family of rhodopsin-like receptors: GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), GPR120 (FFAR4), and several other, less characterized G-protein coupled receptors (GPR84, GPR109A, GPR170, GPR31, GPR132, GPR119, and Olfr78). The ubiquitously distributed FFAR4 can be activated by saturated and unsaturated medium- and long-chain fatty acids (MCFAs and LCFAs), as well as by several synthetic agonists (e.g., TUG-891). The stimulation of FFAR4 using selective synthetic agonists proved to be promising strategy of reduction of inflammatory reactions in various tissues. In this paper, we summarize the evidence showing the mechanisms of the potential beneficial effects of FFAR4 stimulation in atherosclerosis. Based partly on our own results, we also suggest that an important mechanism of such activity may be the modulatory influence of FFAR4 on the phenotype of macrophage involved in atherogenesis. Full article
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Review
Ultrasound Methods in the Evaluation of Atherosclerosis: From Pathophysiology to Clinic
Biomedicines 2021, 9(4), 418; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040418 - 13 Apr 2021
Cited by 1 | Viewed by 1313
Abstract
Atherosclerosis is a key pathological process that causes a plethora of pathologies, including coronary artery disease, peripheral artery disease, and ischemic stroke. The silent progression of the atherosclerotic disease prompts for new surveillance tools that can visualize, characterize, and provide a risk evaluation [...] Read more.
Atherosclerosis is a key pathological process that causes a plethora of pathologies, including coronary artery disease, peripheral artery disease, and ischemic stroke. The silent progression of the atherosclerotic disease prompts for new surveillance tools that can visualize, characterize, and provide a risk evaluation of the atherosclerotic plaque. Conventional ultrasound methods—bright (B)-mode US plus Doppler mode—provide a rapid, cost-efficient way to visualize an established plaque and give a rapid risk stratification of the patient through the Gray–Weale standardization—echolucent plaques with ≥50% stenosis have a significantly greater risk of ipsilateral stroke. Although rather disputed, the measurement of carotid intima-media thickness (C-IMT) may prove useful in identifying subclinical atherosclerosis. In addition, contrast-enhanced ultrasonography (CEUS) allows for a better image resolution and the visualization and quantification of plaque neovascularization, which has been correlated with future cardiovascular events. Newly emerging elastography techniques such as strain elastography and shear-wave elastography add a new dimension to this evaluation—the biomechanics of the arterial wall, which is altered in atherosclerosis. The invasive counterpart, intravascular ultrasound (IVUS), enables an individualized assessment of the anti-atherosclerotic therapies, as well as a direct risk assessment of these lesions through virtual histology IVUS. Full article
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Review
From Mitochondria to Atherosclerosis: The Inflammation Path
Biomedicines 2021, 9(3), 258; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030258 - 05 Mar 2021
Cited by 5 | Viewed by 1159
Abstract
Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable [...] Read more.
Inflammation is a key process in metazoan organisms due to its relevance for innate defense against infections and tissue damage. However, inflammation is also implicated in pathological processes such as atherosclerosis. Atherosclerosis is a chronic inflammatory disease of the arterial wall where unstable atherosclerotic plaque rupture causing platelet aggregation and thrombosis may compromise the arterial lumen, leading to acute or chronic ischemic syndromes. In this review, we will focus on the role of mitochondria in atherosclerosis while keeping inflammation as a link. Mitochondria are the main source of cellular energy. Under stress, mitochondria are also capable of controlling inflammation through the production of reactive oxygen species (ROS) and the release of mitochondrial components, such as mitochondrial DNA (mtDNA), into the cytoplasm or into the extracellular matrix, where they act as danger signals when recognized by innate immune receptors. Primary or secondary mitochondrial dysfunctions are associated with the initiation and progression of atherosclerosis by elevating the production of ROS, altering mitochondrial dynamics and energy supply, as well as promoting inflammation. Knowing and understanding the pathways behind mitochondrial-based inflammation in atheroma progression is essential to discovering alternative or complementary treatments. Full article
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Review
Vitamin D and Its Role in the Lipid Metabolism and the Development of Atherosclerosis
Biomedicines 2021, 9(2), 172; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020172 - 09 Feb 2021
Cited by 7 | Viewed by 1629
Abstract
Vitamin D, a crucial hormone in the homeostasis and metabolism of calcium bone, has lately been found to produce effects on other physiological and pathological processes genomically and non-genomically, including the cardiovascular system. While lower baseline vitamin D levels have been correlated with [...] Read more.
Vitamin D, a crucial hormone in the homeostasis and metabolism of calcium bone, has lately been found to produce effects on other physiological and pathological processes genomically and non-genomically, including the cardiovascular system. While lower baseline vitamin D levels have been correlated with atherogenic blood lipid profiles, 25(OH)D supplementation influences the levels of serum lipids in that it lowers the levels of total cholesterol, triglycerides, and LDL-cholesterol and increases the levels of HDL-cholesterol, all of which are known risk factors for cardiovascular disease. Vitamin D is also involved in the development of atherosclerosis at the site of the blood vessels. Deficiency of this vitamin has been found to increase adhesion molecules or endothelial activation and, at the same time, supplementation is linked to the lowering presence of adhesion surrogates. Vitamin D can also influence the vascular tone by increasing endothelial nitric oxide production, as seen in supplementation studies. Deficiency can lead, at the same time, to oxidative stress and an increase in inflammation as well as the expression of particular immune cells that play a pivotal role in the development of atherosclerosis in the intima of the blood vessels, i.e., monocytes and macrophages. Vitamin D is also involved in atherogenesis through inhibition of vascular smooth muscle cell proliferation. Furthermore, vitamin D deficiency is consistently associated with cardiovascular events, such as myocardial infarction, STEMI, NSTEMI, unstable angina, ischemic stroke, cardiovascular death, and increased mortality after acute stroke. Conversely, vitamin D supplementation does not seem to produce beneficial effects in cohorts with intermediate baseline vitamin D levels. Full article
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