Bromodomain and extra‐terminal protein mimic JQ1 decreases inflammation in human vascular endothelial cells: Implications for pulmonary arterial hypertension

Abstract

Background and objectiveNuclear factor kappa B (NF‐kB)‐mediated inflammatory gene expression and vascular endothelial cell proliferation/remodelling are implicated in the pathophysiology of the fatal disease, pulmonary arterial hypertension (PAH). Bromodomain and extra‐terminal (BET) proteins are essential for the expression of a subset of NF‐kB‐induced inflammatory genes. BET mimics including JQ1+ prevent binding of BETs to acetylated histones and down‐regulate the expression of selected genes.MethodsThe effects of JQ1+ on the proliferation of primary human pulmonary microvascular endothelial cells (HPMECs) from healthy subjects were measured by bromodeoxyuridine (BrdU) incorporation. Cell cycle progression was assessed by flow cytometry; mRNA and protein levels of cyclin‐dependent kinases (CDKs), inhibitors and cytokines were determined by reverse transcription‐quantitative PCR (RT‐qPCR), Western blotting or ELISA. Histone acetyltransferase (HAT) and deacetylase (HDAC) activities were determined in nuclear extracts from whole lung of PAH and control patients.Results JQ1+ significantly inhibited IL6 and IL8 (IL6 and CXCL8) mRNA and protein in HPMECs compared with its inactive enantiomer JQ1−. JQ1+ decreased NF‐kB p65 recruitment to native IL6 and IL8 promoters. JQ1+ showed a concentration‐dependent decrease in HPMEC proliferation compared with JQ1−‐treated cells. JQ1+ induced G1 cell cycle arrest by increasing the expression of the CDK inhibitors (CDKN) 1A (p21cip) and CDKN2D (p19INK4D) and decreasing that of CDK2, CDK4 and CDK6. JQ1+ also inhibited serum‐stimulated migration of HPMECs. Finally, HAT activity was significantly increased in the lung of PAH patients.ConclusionInhibition of BETs in primary HPMECs decreases inflammation and remodelling. BET proteins could be a target for future therapies for PAH.

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

“…44,45 When activated by inflammation or other stimuli, endothelial cells may become dysfunctional and can alter the underlying SMCs by releasing inflammatory cytokines. 45 Interestingly, a recent article by Mumby et al 46 established the implication of BRD4 in triggering the expression of inflammatory genes (IL-6 and IL-8) in human pulmonary microvascular endothelial cells. Also, a recent study suggested that BRD4 plays a role in the atherogenic processes by regulating an inflammatory response in endothelial cells.…”

Potential epigenetic therapeutics for atherosclerosis treatment

“…JQ1 administration (50 mg/kg) reduced aortic plaque area by 40% in cholesterol fed Ldlr −/− mice [98]. It also suppressed p65 recruitment to the IL-6 and IL-8 promoters in human pulmonary microvascular endothelial cells (HPMEC) which inhibited their expression at both the mRNA and protein level [99].…”

Year in review 2017: Interstitial lung disease, pulmonary vascular disease and sleep

“…Mumby et al . found that key enzymes integral in epigenetic regulation are dysfunctional in PAH patients . Furthermore, drugs targeting epigenetic pathways could inhibit inflammation and may therefore provide novel therapeutic options for this devastating condition.…”