Impact of statins on vascular smooth muscle cells and relevance to atherosclerosis

Islam, Torikul

doi:10.1113/jp279774

Cited by 8 publications

(6 citation statements)

References 6 publications

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“…Although we identified the potential involvement of PCSK9i in the regulation of the miR-186-5p/Wipf2 and miR-375-3p/Pdk1/Yap1 axes to exert anti-AS effects, multiple miRNAs are known to regulate the expression of Wipf2, PDK1, and YAP1. Moreover, considering that VSMC migration and phenotypic transition are regulated by various pathways ( 82 , 83 ), the detailed mechanisms underlying PCSK9i’s promotion of AS plaque stability require further exploration.…”

Section: Discussionmentioning

confidence: 99%

PCSK9i promoting the transformation of AS plaques into a stable plaque by targeting the miR-186-5p/Wipf2 and miR-375-3p/Pdk1/Yap1 in ApoE−/− mice

Zhao,

Liu,

Zhang

et al. 2024

Front. Med.

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BackgroundAtherosclerosis (AS) is a multifaceted disease characterized by disruptions in lipid metabolism, vascular inflammation, and the involvement of diverse cellular constituents. Recent investigations have progressively underscored the role of microRNA (miR) dysregulation in cardiovascular diseases, notably AS. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) can effectively reduce circulating levels of low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp (a)], potentially fostering a more enduring phenotype for AS plaques. However, the underlying mechanisms by which PCSK9i enhances plaque stability remain unclear. In this study, we used microarray and bioinformatics techniques to analyze the regulatory impacts on gene expression pertinent to AS, thereby unveiling potential mechanisms underlying the plaque-stabilizing attributes of PCSK9i.MethodsApoE−/− mice were randomly allocated into control, AS, PCSK9i, and Atorvastatin groups. The AS model was induced through a high-fat diet (HFD), succeeded by interventions: the PCSK9i group was subjected to subcutaneous SBC-115076 injections (8 mg/kg, twice weekly), and the Atorvastatin group received daily oral Atorvastatin (10 mg/kg) while on the HFD. Subsequent to the intervention phase, serum analysis, histological assessment using hematoxylin and eosin (H&E) and Oil Red O staining, microarray-centered miRNA analysis utilizing predictions from TargetScan and miRTarBase, and analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were executed to illuminate potential pathways. Real-time fluorescence quantitative PCR (RT-qPCR) was employed to quantify the expression levels of target genes.ResultsIn comparison to the control group, the AS group displayed a significant elevation in blood lipid levels. Both PCSK9i and Atorvastatin effectively attenuated blood lipid levels, with PCSK9i exhibiting a more pronounced lipid-lowering impact, particularly concerning TG and LDL-C levels. Over the course of AS progression, the expression levels of mmu-miR-134, mmu-miR-141-5p, mmu-miR-17-3p, mmu-miR-195-3p, mmu-miR-210, mmu-miR-33–5p, mmu-miR-410, mmu-miR-411-5p, mmu-miR-499, mmu-miR-672-5p, mmu-miR-675-3p, and mmu-miR-301b underwent dynamic fluctuations. PCSK9i significantly down-regulated the expression of mmu-miR-186-5p, mmu-miR-222, mmu-miR-375-3p, and mmu-miR-494-3p. Further enrichment analysis disclosed that mmu-miR-186-5p, mmu-miR-222, mmu-miR-375-3p, and mmu-miR-494-3p were functionally enriched for cardiovascular smooth muscle cell proliferation, migration, and regulation. RT-qPCR results manifested that, in comparison to the AS group, PCSK9i significantly upregulated the expression of Wipf2, Pdk1, and Yap1 (p < 0.05).ConclusionAberrant miRNA expression may play a pivotal role in AS progression in murine models of AS. The subcutaneous administration of PCSK9i exerted anti-atherosclerotic effects by targeting the miR-186-5p/Wipf2 and miR-375-3p/Pdk1/Yap1 axes, thereby promoting the transition of AS plaques into a more stable form.

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Section: Discussionmentioning

confidence: 99%

PCSK9i promoting the transformation of AS plaques into a stable plaque by targeting the miR-186-5p/Wipf2 and miR-375-3p/Pdk1/Yap1 in ApoE−/− mice

Zhao,

Liu,

Zhang

et al. 2024

Front. Med.

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“…Dyslipidemia is one of the major risk factors for the development of cardiometabolic diseases such as diabetes and atherosclerosis 34 , 35 . Our findings demonstrated that RIF was associated with significantly reduced LDL-C, TG, and DG levels while associated with a significant increase in HDL-C ( P = 0.001) levels after 30 days of fasting in overweight and obese individuals.…”

Section: Discussionmentioning

confidence: 99%

Ramadan intermittent fasting is associated with ameliorated inflammatory markers and improved plasma sphingolipids/ceramides in subjects with obesity: lipidomics analysis

Madkour,

Islam,

Tippetts

et al. 2023

Sci Rep

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Intermittent fasting (IF) is associated with enormous metabolic alterations that underpin its diverse health effects. Changes in lipid metabolism, particularly ceramides, and other sphingolipids, are among the most notable of these alterations. This study investigated the lipidomic alterations associated with 29–30 days of Ramadan diurnal intermittent fasting (RIF) in metabolically healthy overweight and obese subjects. A prospective cohort of 57 overweight and obese adults (70% males, 38.4 ± 11.2 years), with an age range of 18–58 years was observed prior to and at the conclusion of Ramadan. At both time points, anthropometric, biochemical (lipid profile, glycemic, and inflammatory markers), and dietary intake measurements were taken. Using liquid chromatography-mass spectrometry, a lipidomic analysis of ceramides and other sphingolipids was conducted. Using paired sample t-tests, pre- and post-Ramadan anthropometric, biochemical, and dietary values were compared. RIF was associated with improved levels of lipid profile compartments and inflammatory markers. In addition, RIF was associated with a decrease in plasma sphingosine and sphinganine, which was accompanied by a decrease in sphingosine 1-phosphate and sphinganine 1-phosphate. In addition, RIF was associated with decreased C17, C22, and C24 sphingomyelin, but not C14, C16, C18, C20, and C24:1 sphingomyelin, as well as C20, C22, C24, and C24:1 dihydrosphingomyelin, but not C16 and C18 dihydrosphingomyelin. This study demonstrates that RIF is associated with improvements in plasma sphingosine, sphinganine sphingomyelin, and dihydrosphingomyelin lipid species, as well as improved lipid profile and inflammatory markers, which may confer short-term protection against cardiometabolic problems in patients with overweight/obesity.

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“…Elevated triglycerides and cholesterols induce endothelial dysfunction leading to LDL infiltration and oxidation in the subintimal layer, triggering monocyte infiltration and differentiation into macrophages [ 1 , 2 ]. Differentiated macrophages engulf oxidized LDL and form foam cells resulting in vascular smooth muscle cell migration and proliferation, platelet aggregation, and sustained inflammation, all of which contribute to the progression of atherosclerosis [ 1 , 2 ]. Our study demonstrates that the atheroprotection in Arf6 heterozygous mice was independent of changes in systemic dyslipidemia and associated with shear sensing, cell migration and proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…Atherosclerosis is an inflammatory arterial disease that is characterized by the deposition of fatty streaks in the lumen of arteries [ 1 – 3 ]. The severity of this disease is determined not only by the size but also by the nature (e.g., composition and stability) of the plaque [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

“…While large plaques may lead to arterial occlusion and cardiovascular events; more commonly, plaque instability leads to plaque rupture or thrombotic events leading to myocardial infarction, stroke, and the associated morbidity and mortality [ 2 ]. Although, numerous hemodynamic and circulating factors contribute to disease progression, dyslipidemia, particularly elevated blood low-density lipoprotein (LDL), is a direct cause of atherosclerosis [ 1 , 2 , 4 , 5 ]. Much of the previous efforts targeting atherosclerotic diseases were focused on lowering cholesterol, resulting in the emergence of cholesterol lowering drugs such as statins [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis

Gogulamudi,

Islam,

Durrant

et al. 2023

PLoS ONE

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Atherosclerosis is the root cause of major cardiovascular diseases (CVD) such as myocardial infarction and stroke. ADP-ribosylation factor 6 (Arf6) is a ubiquitously expressed GTPase known to be involved in inflammation, vascular permeability and is sensitive to changes in shear stress. Here, using atheroprone, ApoE-/- mice, with a single allele deletion of Arf6 (HET) or wildtype Arf6 (WT), we demonstrate that reduction in Arf6 attenuates atherosclerotic plaque burden and severity. We found that plaque burden in the descending aorta was lower in HET compared to WT mice (p˂0.001) after the consumption of an atherogenic Paigen diet for 5 weeks. Likewise, luminal occlusion, necrotic core size, plaque grade, elastic lamina breaks, and matrix deposition were lower in the aortic root atheromas of HET compared to WT mice (all p≤0.05). We also induced advanced human-like complex atherosclerotic plaque in the left carotid artery using partial carotid ligation surgery and found that atheroma area, plaque grade, intimal necrosis, intraplaque hemorrhage, thrombosis, and calcification were lower in HET compared to WT mice (all p≤0.04). Our findings suggest that the atheroprotection afforded by Arf6 heterozygosity may result from reduced immune cell migration (all p≤0.005) as well as endothelial and vascular smooth muscle cell proliferation (both p≤0.001) but independent of changes in circulating lipids (all p≥0.40). These findings demonstrate a critical role for Arf6 in the development and severity of atherosclerosis and suggest that Arf6 inhibition can be explored as a novel therapeutic strategy for the treatment of atherosclerotic CVD.

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Impact of statins on vascular smooth muscle cells and relevance to atherosclerosis

Cited by 8 publications

References 6 publications

PCSK9i promoting the transformation of AS plaques into a stable plaque by targeting the miR-186-5p/Wipf2 and miR-375-3p/Pdk1/Yap1 in ApoE−/− mice

PCSK9i promoting the transformation of AS plaques into a stable plaque by targeting the miR-186-5p/Wipf2 and miR-375-3p/Pdk1/Yap1 in ApoE−/− mice

Ramadan intermittent fasting is associated with ameliorated inflammatory markers and improved plasma sphingolipids/ceramides in subjects with obesity: lipidomics analysis

Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis

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