P ulmonary arterial hypertension (PAH) is an obstructive vascular pathology affecting the small pulmonary arteries (PAs). It is characterized by enhanced inflammation, vasoconstriction, and proliferation/apoptosis imbalance within the artery wall, leading to increased pulmonary vascular resistance, right ventricular (RV) failure and death.1 PAH is a rare disease with an estimated prevalence of 15 to 50 cases/million 2 and its prevalence is thought to be highly underestimated [3][4][5][6] because of lack of symptom specificity. Despite recent therapeutic advances using vasodilator therapies, 1 most patients exhibit persistent poor exercise capacity and quality of life and their prognosis remains poor with a 3-year survival of 55% to 65%. 4,6,7 As in cancer, PAH is associated with sustained DNA damage, which accounts for a poly(ADP ribose) polymerase 1-dependent downregulation of and the activation of the nuclear factor of activated T cells (NFATs).8 The miR-204/NFAT axis affects mitochondrial function, bioenergetic profile and promotes the expression of oncogenes implicated in PAH, including B-cell lymphoma 2 (Bcl-2) and Survivin. 9,10 This results in the proproliferative and antiapoptotic phenotype of PAH pulmonary artery smooth muscle cells (PASMCs).

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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.

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