tretinoin and Coronary-Artery-Disease

GWAS and eQTL studies identified thousands of genetic variants associated with complex traits and gene expression. Despite the important role of environmental exposures in complex traits, only a limited number of environmental factors were measured in these studies. Measuring molecular phenotypes in tightly controlled cellular environments provides a more tractable setting to study gene-environment interactions in the absence of other confounding variables. We performed RNA-seq and ATAC-seq in endothelial cells exposed to retinoic acid, dexamethasone, caffeine, and selenium to model genetic and environmental effects on gene regulation in the vascular endothelium-a common site of pathology in cardiovascular disease. We found that genes near regions of differentially accessible chromatin were more likely to be differentially expressed [OR = (3.41, 6.52), [Formula: see text]]. Furthermore, we confirmed that environment-specific changes in transcription factor binding are a key mechanism for cellular response to environmental stimuli. Single nucleotide polymorphisms (SNPs) in these transcription response factor footprints for dexamethasone, caffeine, and retinoic acid were enriched in GTEx eQTLs from artery tissues, indicating that these environmental conditions are latently present in GTEx samples. Additionally, SNPs in footprints for response factors in caffeine are enriched in colocalized eQTLs for coronary artery disease (CAD), suggesting a role for caffeine in CAD risk. By combining GWAS, eQTLs, and response genes, we annotated environmental components that can increase or decrease disease risk through changes in gene expression in 43 genes. Interestingly, each treatment may amplify or buffer genetic risk for CAD, depending on the particular SNP or gene considered.

Topics: Caffeine; Coronary Artery Disease; Endothelial Cells; Gene Expression Regulation; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Phenotype; Quantitative Trait Loci; Risk Factors; RNA-Seq; Selenium; Tretinoin

Retinoic acid (RA) and its mediated nuclear receptor signaling have broad protective effects on vascular systems. Whether circulating levels of RA are associated with mortality in patients with coronary artery disease is still unknown.. To evaluate the association of circulating RA with the risk of mortality.. We measured serum RA concentrations in 1499 patients with angiographically confirmed coronary artery disease (mean age, 61 years; male, 67%) recruited from October 2008 and December 2011 in the Guangdong Coronary Artery Disease Cohort. During a median (interquartile range) period of 4.4 (3.6 to 6.1) years of follow-up, there were 295 all-cause mortality, among which 208 had cardiovascular mortality. Serum RA level was significantly lower in participants with mortality (median 21 [11-47] nmol/L) than in those without mortality (median 39 [19-86] nmol/L). In multivariate analyses, the hazard ratios for total mortality among those in the lowest (referent) to highest quartiles of serum RA measured at study entry were 1.0, 0.83, 0.74, and 0.56, respectively (P-trend<0.001). For cardiovascular mortality, the comparable hazard ratios were 1.0, 0.76, 0.69, and 0.60 (P-trend<0.001). Furthermore, high RA levels (defined as >median) were associated with lower risk of total mortality (adjusted hazard ratios, 0.68; 95% confidence interval, 0.50-0.85; P=0.001) and cardiovascular mortality (adjusted hazard ratios, 0.62; 95% confidence interval, 0.45-0.78; P<0.001) compared with low RA (defined as ≤median).. Serum RA level was associated with lower risk of mortality in a population-based coronary artery disease cohort.

Topics: Aged; Biomarkers; Cohort Studies; Coronary Artery Disease; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mortality; Prospective Studies; Risk Factors; Tretinoin

Coronary atherosclerosis can lead to myocardial infarction, and secondarily to post-infarct remodelling and heart failure. Retinoic acid (RA) influences cell proliferation. We hypothesized that RA could influence gene expression and proliferation of cardiovascular cells. Left ventricular biopsies from patients with end-stage heart failure due to coronary artery disease (CAD) or dilated cardiomyopathy were investigated for the content of RA metabolites using liquid chromatography mass spectrometry (LC-MS/MS), and compared with healthy donors. All-trans retinoic acid (ATRA) was increased in the hearts of CAD patients. Gene expression (quantitative PCR) of RA target genes was not influenced in failing hearts, but was increased in the hearts of patients with CAD undergoing open heart surgery. The expression of RA target genes was increased in atherosclerotic lesions from carotid arteries compared to healthy arteries. Stimulation of cardiomyocytes, cardiofibroblasts, smooth muscle cells and endothelial cells with ATRA increased the gene expression of the key enzymes. Cardiofibroblast and smooth muscle cell proliferation were reduced by ATRA, which increased endothelial cell proliferation. Coronary artery disease leads to increased expression of RA target genes. ATRA accumulated in the failing human heart. All investigated cell types present in the heart had induced expression of RA target genes when stimulated with ATRA, which also influenced cell proliferation.

Topics: Biopsy; Cell Differentiation; Cell Proliferation; Coronary Artery Disease; Fibroblasts; Gene Expression Regulation; Heart Ventricles; Humans; Myocardial Infarction; Myocardium; Myocytes, Smooth Muscle; Receptors, Retinoic Acid; Tandem Mass Spectrometry; Tretinoin

Circulating CD34+ progenitor cells have the potential to differentiate into a variety of cells, including endothelial cells. Knowledge is still scarce about the transcriptional programs used by CD34+ cells from peripheral blood, and how these are affected in coronary artery disease (CAD) patients.. We performed a whole genome transcriptome analysis of CD34+ cells, CD4+ T cells, CD14+ monocytes, and macrophages from 12 patients with CAD and 11 matched controls. CD34+ cells, compared to other mononuclear cells from the same individuals, showed high levels of KRAB box transcription factors, known to be involved in gene silencing. This correlated with high expression levels in CD34+ cells for the progenitor markers HOXA5 and HOXA9, which are known to control expression of KRAB factor genes. The comparison of expression profiles of CD34+ cells from CAD patients and controls revealed a less naïve phenotype in patients' CD34+ cells, with increased expression of genes from the Mitogen Activated Kinase network and a lowered expression of a panel of histone genes, reaching levels comparable to that in more differentiated circulating cells. Furthermore, we observed a reduced expression of several genes involved in CXCR4-signaling and migration to SDF1/CXCL12.. The altered gene expression profile of CD34+ cells in CAD patients was related to activation/differentiation by a retinoic acid-induced differentiation program. These results suggest that circulating CD34+ cells in CAD patients are programmed by retinoic acid, leading to a reduced capacity to migrate to ischemic tissues.

Topics: Antigens, CD34; Case-Control Studies; Cell Differentiation; Cell Movement; Coronary Artery Disease; Gene Expression Profiling; Genomics; Humans; Phenotype; Stem Cells; Tretinoin