TCF21 and the environmental sensor aryl-hydrocarbon receptor cooperate to activate a pro-inflammatory gene expression program in coronary artery smooth muscle cells.
2017; 13 (5)
Genetics and Genomics of Coronary Artery Disease.
Current cardiology reports
2016; 18 (10): 102-?
Both environmental factors and genetic loci have been associated with coronary artery disease (CAD), however gene-gene and gene-environment interactions that might identify molecular mechanisms of risk are not easily studied by human genetic approaches. We have previously identified the transcription factor TCF21 as the causal CAD gene at 6q23.2 and characterized its downstream transcriptional network that is enriched for CAD GWAS genes. Here we investigate the hypothesis that TCF21 interacts with a downstream target gene, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that mediates the cellular response to environmental contaminants, including dioxin and polycyclic aromatic hydrocarbons (e.g., tobacco smoke). Perturbation of TCF21 expression in human coronary artery smooth muscle cells (HCASMC) revealed that TCF21 promotes expression of AHR, its heterodimerization partner ARNT, and cooperates with these factors to upregulate a number of inflammatory downstream disease related genes including IL1A, MMP1, and CYP1A1. TCF21 was shown to bind in AHR, ARNT and downstream target gene loci, and co-localization was noted for AHR-ARNT and TCF21 binding sites genome-wide in regions of HCASMC open chromatin. These regions of co-localization were found to be enriched for GWAS signals associated with cardio-metabolic as well as chronic inflammatory disease phenotypes. Finally, we show that similar to TCF21, AHR gene expression is increased in atherosclerotic lesions in mice in vivo using laser capture microdissection, and AHR protein is localized in human carotid atherosclerosis lesions where it is associated with protein kinases with a critical role in innate immune response. These data suggest that TCF21 can cooperate with AHR to activate an inflammatory gene expression program that is exacerbated by environmental stimuli, and may contribute to the overall risk for CAD.
View details for DOI 10.1371/journal.pgen.1006750
View details for PubMedID 28481916
Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci.
2016; 7: 12092-?
Coronary artery disease (or coronary heart disease), is the leading cause of mortality in many of the developing as well as the developed countries of the world. Cholesterol-enriched plaques in the heart's blood vessels combined with inflammation lead to the lesion expansion, narrowing of blood vessels, reduced blood flow, and may subsequently cause lesion rupture and a heart attack. Even though several environmental risk factors have been established, such as high LDL-cholesterol, diabetes, and high blood pressure, the underlying genetic composition may substantially modify the disease risk; hence, genome composition and gene-environment interactions may be critical for disease progression. Ongoing scientific efforts have seen substantial advancements related to the fields of genetics and genomics, with the major breakthroughs yet to come. As genomics is the most rapidly advancing field in the life sciences, it is important to present a comprehensive overview of current efforts. Here, we present a summary of various genetic and genomics assays and approaches applied to coronary artery disease research.
View details for DOI 10.1007/s11886-016-0777-y
View details for PubMedID 27586139
Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci
2015; 11 (5)
Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.
View details for DOI 10.1038/ncomms12092
View details for PubMedID 27386823
Coronary Artery Disease Associated Transcription Factor TCF21 Regulates Smooth Muscle Precursor Cells That Contribute to the Fibrous Cap
2015; 11 (5)
Continuous flow left ventricular assist device placement complicated by aortic valve thrombus and myocardial infarction
INTERNATIONAL JOURNAL OF CARDIOLOGY
2014; 176 (3): E102-E103
Presence of plaques predicts worse outcomes in multi-detector computed tomography in patients with stable chest pain syndrome
INTERNATIONAL JOURNAL OF CARDIOLOGY
2014; 173 (3): 570-572
Heart Failure is Associated With Impaired Anti-Inflammatory and Antioxidant Properties of High-Density Lipoproteins
AMERICAN JOURNAL OF CARDIOLOGY
2013; 112 (11): 1770-1777
To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.
View details for DOI 10.1371/journal.pgen.1005202
View details for Web of Science ID 000355305200022
View details for PubMedID 26020271
Anti-Inflammatory Strategies for Plaque Stabilization after Acute Coronary Syndromes
CURRENT ATHEROSCLEROSIS REPORTS
2013; 15 (6)
Oxidative stress and inflammation are hallmarks of the heart failure (HF) disease state. In the present study, we investigated the inflammatory/anti-inflammatory characteristics of high-density lipoproteins (HDL) in patients with HF. Ninety-six consecutive patients with systolic HF were followed in an advanced HF center, and 21 healthy subjects were recruited. Plasma was tested for HDL inflammatory index (HII) using a monocyte chemotactic activity assay, with HII >1.0 indicating proinflammatory HDL. We found significantly increased inflammatory properties of HDL in patients with HF (median HII 1.56 vs 0.59 in controls; p <0.0001). Serum amyloid A level was markedly elevated and the activity of paraoxonase-1, an HDL antioxidant enzyme, was significantly reduced in patients versus controls. HDL and albumin from patients with HF contained markedly elevated levels of oxidized products of arachidonic and linoleic acids. HDL function improved when plasma was treated in vitro with 4F, an apolipoprotein A-I mimetic peptide (40% reduction in HII, p <0.0001). There was no correlation found between HII level and ejection fraction or New York Heart Association functional class. In conclusion, HDL function is significantly impaired and oxidation products of arachidonic and linoleic acids are markedly elevated in patients with HF compared with non-HF controls.
View details for DOI 10.1016/j.amjcard.2013.07.045
View details for Web of Science ID 000327685900012
View details for PubMedID 24050409
Effect of 9p21.3 coronary artery disease locus neighboring genes on atherosclerosis in mice.
2012; 126 (15): 1896-1906
Despite dramatic advances in standard of care, the risk of recurrent myocardial infarction early after an acute coronary syndrome (ACS) remains high. This period of elevated risk after a cardiovascular event is associated with an acute inflammatory response. While post-ACS inflammation correlates with the risk for recurrent events and is likely to play a causal role in this period, the precise pathophysiologic mechanisms have been unclear. Recent studies have proposed that the cardiac event itself activates the sympathetic nervous system to directly mobilize hematopoietic stem cells to differentiate into inflammatory monocytes, acutely infiltrate plaque, and lead to recurrent plaque rupture. Here, we summarize the existing and emerging evidence implicating post-ACS activation of systemic inflammation in the progression of atherosclerosis, and identify possible targets for therapeutic intervention. We highlight experimental therapies and ongoing clinical studies that will validate these targets.
View details for DOI 10.1007/s11883-013-0327-7
View details for Web of Science ID 000320656500002
View details for PubMedID 23636864
Paraoxonase-2 Modulates Stress Response of Endothelial Cells to Oxidized Phospholipids and a Bacterial Quorum-Sensing Molecule
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2011; 31 (11): 2624-U688
The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large-scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap, the 2 isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b, in atherosclerosis using knockout mice models.Gene-targeted mice for neighboring genes, including Mtap, Cdkn2a, p19Arf, and Cdkn2b, were each bred to mice carrying the human APO*E3 Leiden transgene that sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesions compared with wild-type mice (49623±21650 versus 18899±9604 μm(2) per section [mean±SD]; P=0.01), with morphology similar to that of wild-type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles and CD4(+) cell counts. The Cdkn2a knockout mice had smaller lesions compared with wild-type and heterozygous mice, and there were no significant differences in lesion size in p19Arf and Cdkn2b mutants compared with wild type. We observed extensive, tissue-specific compensatory regulation of the Cdkn2a and Cdkn2b genes among the various knockout mice, making the effects on atherosclerosis difficult to interpret.Mtap plays a protective role against atherosclerosis, whereas Cdkn2a appears to be modestly proatherogenic. However, no relation was found between the 9p21 genotype and the transcription of 9p21 neighboring genes in primary human aortic vascular cells in vitro. There is extensive compensatory regulation in the highly conserved 9p21 orthologous region in mice.
View details for DOI 10.1161/CIRCULATIONAHA.111.064881
View details for PubMedID 22952318
Dyslipidemia and cardiovascular diseases
CURRENT OPINION IN LIPIDOLOGY
2009; 20 (2): 157-158
The effect of transvenous pacemaker and implantable cardioverter defibrillator lead placement on tricuspid valve function: An observational study
JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY
2008; 21 (3): 284-287
Chronic infection has long been postulated as a stimulus for atherogenesis. Pseudomonas aeruginosa infection has been associated with increased atherosclerosis in rats, and these bacteria produce a quorum-sensing molecule 3-oxo-dodecynoyl-homoserine lactone (3OC12-HSL) that is critical for colonization and virulence. Paraoxonase 2 (PON2) hydrolyzes 3OC12-HSL and also protects against the effects of oxidized phospholipids thought to contribute to atherosclerosis. We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression.Using expression profiling and network modeling, we identified the unfolded protein response (UPR), cell cycle genes, and the mitogen-activated protein kinase signaling pathway to be heavily involved in the HAEC response to 3OC12-HSL. The network also showed striking similarities to a network created based on HAEC response to Ox-PAPC, a major component of minimally modified low-density lipoprotein. HAECs in which PON2 was silenced by small interfering RNA showed increased proinflammatory response and UPR when treated with 3OC12-HSL or Ox-PAPC.3OC12-HSL and Ox-PAPC influence similar inflammatory and UPR pathways. Quorum sensing molecules, such as 3OC12-HSL, contribute to the proatherogenic effects of chronic infection. The antiatherogenic effects of PON2 include destruction of quorum sensing molecules.
View details for DOI 10.1161/ATVBAHA.111.232827
View details for Web of Science ID 000296605400037
View details for PubMedID 21836061
This study assessed the effect of transtricuspid placement of permanent pacemaker (PPM) and implantable cardioverter defibrillator (ICD) leads on tricuspid regurgitation (TR) in 248 patients with echocardiograms before and after placement. Some 21.2% of patients with baseline mild TR or less developed abnormal TR (3.4% mild-moderate, 12.8% moderate, 1.1% moderate-severe, 3.9% severe) after implant. TR worsened by 1 grade or more after implant in 24.2% (20.7% of PPMs vs. 32.4% of ICDs; P < .05). TR worsening was more common with ICDs than PPMs in patients with baseline mild TR or less. After lead implantation, abnormal TR developed in 21.2% and severe TR developed in 3.9% of patients with initially normal TR. TR worsened by at least 1 grade in 24.2%. Patients with ICDs had a higher rate of TR worsening compared with patients with PPMs (32.4% vs. 20.1%; P < .05).
View details for DOI 10.1016/j.echo.2007.05.022
View details for Web of Science ID 000254081900014
View details for PubMedID 17604958