Bromodomain-Containing Protein 4

Abstract

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).

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

“…BRD4 inhibition was also associated with improvements in hemodynamic measurements (mean pulmonary artery pressures of 16, 54, 50, 29, 54, and 36 mm Hg for Control, Sugen-PAH, Sugen-PAH+scrambled siRNA, Sugen-PAH+siBRD4, Sugen-PAH+dimethyl sulfoxide, and Sugen-PAH+JQ1, respectively) and lung vascular remodeling. 12 We also observed that siBRD4-treated rats exhibited over 50% knockdown of BRD4-positive cells within their coronary arteries ( Figure IID in the online-only Data Supplement). This may be attributable to the decrease in IL-6 levels within heart tissues, as shown below, or through other feedback loops that still need to be investigated.…”

“…We observed that BRD4, which is increased in the lungs of patients with PAH, 12 is also overexpressed in their coronary arteries and is responsible, at least in part, for triggering vascular remodeling processes and increasing the risk of these patients to develop MVD or CAD. We showed that coronary arteries of patients with PAH, regardless of their location within the heart (RV or left ventricle), had greater wall thickness ( Figure 1A; Figure IA in the online-only Data Supplement), exhibited increased inflammation (IL-6, Figure 1D), sustained DNA damage ( Figure 1F), and significantly more BRD4-expressing cells (Figure 2A; Figure IIA in the online-only Data Supplement).…”

“…15 Interestingly, these proinflammatory cytokines are upregulated in PAH 16 and are known to cause DNA damage. 9 Thus, BRD4 is a key regulator of the proliferation/apoptosis balance 12,13 by modulating gene expression and plays a critical role in post-DNA damage events. 17 In cancer, BRD4 is a known trigger of the osteogenic factor Runt-related transcription factor 2 expression, 18,19 which was recently associated with PAH lung abnormalities (including proliferation and calcification), 20 and, interestingly, BRD4 inhibition by JQ1 suppressed vascular calcification/atherogenic processes in a hypercholesterolemic murine model.…”

“…17 In cancer, BRD4 is a known trigger of the osteogenic factor Runt-related transcription factor 2 expression, 18,19 which was recently associated with PAH lung abnormalities (including proliferation and calcification), 20 and, interestingly, BRD4 inhibition by JQ1 suppressed vascular calcification/atherogenic processes in a hypercholesterolemic murine model. 15 Furthermore, in addition to promoting DNA damage, 17 atherogenic processes 15 and increased proliferation, 12,13 BRD4 is also associated with inflammation, diabetes mellitus, obesity, and metabolic abnormalities, 13 all playing a role in VRDs, and particularly in coronary artery disease (CAD). 21,22 Heart diseases are the leading global cause of death in both men and women in industrialized countries.…”

“…These rats were used in a previous publication 12 where we measured the therapeutic potential of BRD4 inhibition on lung alterations in PAH. Nevertheless, the coronary circulation of these rats was not explored in the framework of that study.…”