Role for DNA damage and epigenetic signaling in coronary artery diseases

Abstract

Coronary artery disease (CAD) is the most common cause of heart attacks. Evidence demonstrated that coronary artery stenosis have increased inflammation leading to sustained DNA damage. In cancer, through the activation of poly(ADP)ribose‐polymerase 1 (PARP‐1), a critical enzyme acting as a DNA damage sensor, and the epigenetic reader Bromodomain‐containing protein 4 (BRD4), DNA damage promotes mitochondrial/metabolic dysfunction contributing to cell proliferation. Thus, we hypothesized that increased inflammation‐induced DNA damage in remodeled coronary arteries promotes BRD4 and PARP‐1 expression, triggering CoASMC proliferation. Both coronary arteries (n=10) and primary cultured CoASMC (n=4) from patients with stenosis exhibit increased (p<0.05) DNA damage (γ‐H2AX and 53BP1), PARP‐1 and BRD4 protein expression (western blot). This pathological phenotype significantly increased (p<0.05) cell proliferation (Ki67, MTT assay) through a mitochondrial (TMRM) and metabolic dysfunction (Seahorse XFe24) compared to control cells (n=3). Furthermore, co‐culture of CoASMC with peripheral blood mononuclear cells (PBMC) isolated from symptomatic CAD patients promotes BRD4 expression (qRT‐PCR). Finally, experimental rat model of carotid angioplasty exhibit a similar phenotype that the one seen in CAD patients. Our study suggests an important role for PARP‐1/BRD4 axis in CoASMC proliferation in CAD.A “Fonds de recherche Quebec‐Sante” graduate scholarship to Jolyane Meloche, as well as Canadian Institutes of Health Research grants and a Canadian Research Chair in Vascular Remodeling Diseases to Sebastien Bonnet supported this work.