Cellular and molecular mechanisms of statins: an update on pleiotropic effects

Coronary artery disease (CAD) is the leading cause of death worldwide. The efficacy and safety of statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) in primary and secondary prevention of CAD are confirmed in several large studies. It is well known that statins have some pleiotropic, anti-atherosclerotic effects. We review the molecular mechanisms underlying the beneficial effects of statins revealed in recently published studies. Endothelial cell injury is regarded as the classic stimulus for the development of atherosclerotic lesions. In addition, the inflammatory process plays an important role in the aetiology of atherosclerosis. In particular, chronic inflammation plays a key role in coronary artery plaque instability and subsequent occlusive thrombosis. Our previous reports and others have demonstrated beneficial effects of statins on endothelial dysfunction and chronic inflammation in CAD. A better understanding of the molecular mechanism underlying the effectiveness of statins against atherosclerosis may provide a novel therapeutic agent for the treatment of coronary atherosclerosis. The present review summarizes the cellular and molecular mechanism of statins against coronary atherosclerosis.

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Abstract 6133: Microvascular Dysfunction and Chronic Inflammation in Patients without Cardiovascular Risk Factors

Circulation ◽

10.1161/circ.118.suppl_18.s_1068-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Alejandro Recio-Mayoral ◽

Justin C Mason ◽

Juan C Kaski ◽

Michael B Rubens ◽

Olivier A Harari ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Cardiovascular Risk ◽

Coronary Artery ◽

Cardiovascular Risk Factors ◽

Chronic Inflammation ◽

Coronary Atherosclerosis ◽

Microvascular Dysfunction ◽

Early Marker ◽

Artery Disease

Premature coronary atherosclerosis, which is actually seen as an active inflammatory process, is an established complication of systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We hypothesized that exposure to chronic inflammation, even in the absence of classical cardiovascular risk factors (CVRF), could result in coronary microvascular dysfunction (CMD), an early marker of coronary atherosclerosis. By means of positron emission tomography in combination with oxygen-15 labeled water, myocardial blood flow (MBF) was measured at rest and during iv adenosine infusion (140 μg/kg/min) in 13 SLE and 12 RA patients (mean [±SD] age 44±10 years) without CVRF. All patients underwent coronary angiography using multi-slice (64 slices) computed tomography and only those with none or trivial coronary artery disease (<30% luminal stenosis) were included. A group of 25 age- and gender-matched controls were also studied. There were no differences between patients and controls regarding body-mass index, blood pressure and lipid parameters. RA and SLE patients showed similar mean disease duration (16±11 and 11±7 years, respectively; p=0.12). Resting MBF was similar in patients and controls (1.25±0.27 vs 1.15±0.24 ml/min/g, p=0.15). However, during adenosine stress patients had lower MBF compared with controls (2.94±0.83 vs 4.11±0.84 ml/min/g, p<0.001). As result, coronary flow reserve (CFR; adenosine/resting MBF) was significantly reduced in patients (2.44±0.78) compared with controls (3.81±1.07; p<0.001). Seven patients showed ischemic electrocardiographic changes during adenosine and had a more severe reduction in CFR (1.76±0.81) and more years of disease (21±7 years) compared with those patients without ischemic changes (CFR 2.49±0.54; p=0.006; duration of disease 14±5 years; p=0.03). CFR was inversely correlated with years of disease (r=−0.65, p<0.001), but not with corticosteroid cumulative dose (r=0.20, p=0.39). Chronic inflammation in the absence of traditional CVRF is characterized by severe CMD. This may represent an early marker of disease which precedes and contributes to premature coronary artery disease in patients with RA and SLE.

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Analysis of Differentially Expressed Genes in Coronary Artery Disease by Integrated Microarray Analysis

Biomolecules ◽

10.3390/biom10010035 ◽

2019 ◽

Vol 10 (1) ◽

pp. 35 ◽

Cited By ~ 1

Author(s):

Meenashi Vanathi Balashanmugam ◽

Thippeswamy Boreddy Shivanandappa ◽

Sivagurunathan Nagarethinam ◽

Basavaraj Vastrad ◽

Chanabasayya Vastrad

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Molecular Mechanism ◽

Differentially Expressed Genes ◽

Regulatory Network ◽

Molecular Mechanisms ◽

Target Genes ◽

Interaction Network ◽

Differentially Expressed ◽

Artery Disease

Coronary artery disease (CAD) is a major cause of end-stage cardiac disease. Although profound efforts have been made to illuminate the pathogenesis, the molecular mechanisms of CAD remain to be analyzed. To identify the candidate genes in the advancement of CAD, microarray dataset GSE23766 was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified, and pathway and gene ontology (GO) enrichment analyses were performed. The protein-protein interaction network was constructed and the module analysis was performed using the Biological General Repository for Interaction Datasets (BioGRID) and Cytoscape. Additionally, target genes-miRNA regulatory network and target genes-TF regulatory network were constructed and analyzed. There were 894 DEGs between male human CAD samples and female human CAD samples, including 456 up regulated genes and 438 down regulated genes. Pathway enrichment analyses revealed that DEGs (up and down regulated) were mostly enriched in the superpathway of steroid hormone biosynthesis, ABC transporters, oxidative ethanol degradation III and Complement and coagulation cascades. Similarly, geneontology enrichment analyses revealed that DEGs (up and down regulated) were mostly enriched in the forebrain neuron differentiation, filopodium membrane, platelet degranulation and blood microparticle. In the PPI network and modules (up and down regulated), MYC, NPM1, TRPC7, UBC, FN1, HEMK1, IFT74 and VHL were hub genes. In the target genes-miRNA regulatory network and target genes—TF regulatory network (up and down regulated), TAOK1, KHSRP, HSD17B11 and PAH were target genes. In conclusion, the pathway and GO ontology enriched by DEGs may reveal the molecular mechanism of CAD. Its hub and target genes, MYC, NPM1, TRPC7, UBC, FN1, HEMK1, IFT74, VHL, TAOK1, KHSRP, HSD17B11 and PAH were expected to be new targets for CAD. Our finding provided clues for exploring molecular mechanism and developing new prognostics, diagnostic and therapeutic strategies for CAD.

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The Role of Endothelial Progenitor Cells in Coronary Artery Disease: Basic Molecular Mechanisms and Its Clinical Potentials

The Indonesian Biomedical Journal ◽

10.18585/inabj.v13i2.1570 ◽

2021 ◽

Vol 13 (2) ◽

pp. 106-13

Author(s):

Yudi Her Oktaviono ◽

Suryo Ardi Hutomo ◽

Kevin Luke

Keyword(s):

Coronary Artery Disease ◽

Coronary Artery ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Molecular Mechanisms ◽

Endothelial Progenitor ◽

Beneficial Effects ◽

Endothelial Colony Forming Cells ◽

Artery Disease ◽

Universal Definition

BACKGROUND: Coronary artery disease (CAD) remains as the world number one cause of morbidity and mortality. Endothelial progenitor cells (EPCs) are known to be involved in vascular biology. Current review briefly summarizes the basics of EPCs and its clinical use in CAD.CONTENT: EPCs were firstly isolated in 1997 and involved in neovascularization. Further evidence defined EPCs into two distinguishable groups, namely: myeloid angiogenic cells (MACs) and endothelial colony forming cells (ECFCs). Common cardiovascular drugs, statin, angiotensin-converting enzyme (ACE) inhibitor, and their combinations, showed beneficial effects on EPCs. Likewise, the incorporation of EPCs upon CAD intervention management had been recently studied. Intramyocardial EPCs implementation and anti-CD34 antibody-coated stents could provide a promising option for refractory symptoms in CAD.SUMMARY: Association between EPCs and CAD is very dynamic and complex. EPCs could serve as both therapeutic target and agent in CAD patients. Subsequently, a universal definition of EPCs is needed for greater research in the future.KEYWORDS: atherosclerosis, coronary artery disease, endothelial progenitor cells, neovascularization

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Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

Clinical Science ◽

10.1042/cs20190999 ◽

2019 ◽

Vol 133 (22) ◽

pp. 2283-2299

Author(s):

Apabrita Ayan Das ◽

Devasmita Chakravarty ◽

Debmalya Bhunia ◽

Surajit Ghosh ◽

Prakash C. Mandal ◽

...

Keyword(s):

Risk Factors ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Chronic Inflammation ◽

Ex Vivo ◽

Human Subjects ◽

Critical Role ◽

Atherosclerotic Cardiovascular Disease ◽

Tnf Α ◽

Artery Disease

Abstract The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P<0.05) higher in clinical (2342 ± 184 pg/ml) and subclinical cases (1773 ± 118 pg/ml) than healthy controls (461 ± 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fcɣ receptor I (FcɣRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcɣR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis.

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