Reciprocal regulation of endothelial–mesenchymal transition by MAPK7 and EZH2 in intimal hyperplasia and coronary artery disease

Endothelial–mesenchymal transition (EndMT) is a form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose endothelial functions, which contributes to the pathogenesis of intimal hyperplasia and atherosclerosis. The mitogen activated protein kinase 7 (MAPK7) inhibits EndMT and decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (EZH2), thereby maintaining endothelial quiescence. EZH2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). It is elusive how the crosstalk between MAPK7 and EZH2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed in vascular disease. In human coronary artery disease, we assessed the expression levels of MAPK7 and EZH2 and found that with increasing intima/media thickness ratio, MAPK7 expression decreased, whereas EZH2 expression increased. In vitro, MAPK7 activation decreased EZH2 expression, whereas endothelial cells deficient of EZH2 had increased MAPK7 activity. MAPK7 activation results in increased expression of microRNA (miR)-101, a repressor of EZH2. This loss of EZH2 in turn results in the increased expression of the miR-200 family, culminating in decreased expression of the dual-specificity phosphatases 1 and 6 who may repress MAPK7 activity. Transfection of endothelial cells with miR-200 family members decreased the endothelial sensitivity to TGFβ1-induced EndMT. In endothelial cells there is reciprocity between MAPK7 signaling and EZH2 expression and disturbances in this reciprocal signaling associate with the induction of EndMT and severity of human coronary artery disease.

Low Levels of MicroRNA-10a in Cardiovascular Endothelium and Blood Serum Are Related to Human Atherosclerotic Disease

Background. MicroRNA-10a (miR-10a) inhibits transcriptional factor GATA6 to repress inflammatory GATA6/VCAM-1 signaling, which is regulated by blood flow to affect endothelial function/dysfunction. This study aimed to identify the expression patterns of miR-10a/GATA6/VCAM-1 in vivo and study their implications in the pathophysiology of human coronary artery disease (CAD), i.e., atherosclerosis. Methods. Human atherosclerotic coronary arteries and nondiseased arteries were used to detect the expressions of miR-10a/GATA6/VCAM-1 in pathogenic vs. normal conditions. In addition, sera from CAD patients and healthy subjects were collected to detect the level of circulating miR-10a. Results. The comparison of human atherosclerotic coronary arteries with nondiseased arteries demonstrated that lower levels of endothelial miR-10a are related to human atherogenesis. Moreover, GATA6/VCAM-1 (a downstream target of miR-10a) was highly expressed in the endothelium, accompanied by the reduced levels of miR-10a during the development of human atherosclerosis. In addition, CAD patients had a significantly lower concentration of miR-10a in their serum compared to healthy subjects. Conclusions. Our findings suggest that low miR-10a and high GATA6/VCAM-1 in the cardiovascular endothelium correlates to the development of human atherosclerotic lesions, suggesting that miR-10a signaling has the potential to be developed as a biomarker for human atherosclerosis.

SVEP1, a novel human coronary artery disease locus, promotes atherosclerosis

SummaryA low-frequency variant of SVEP1, an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, however, it was unclear if and how SVEP1 might contribute to atherosclerosis. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice. We find that SVEP1 is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1, and is further increased by the coronary disease-associated SVEP1 variant. These effects ultimately drive inflammation and promote atherosclerosis. Taken together, our results suggest that VSMC-derived SVEP1 is a pro-atherogenic factor, and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.