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

• DOI: 10.1111/resp.12872
• Publication Date: 2016-08-19T01:26:39Z
• Authors: Sharon Mumby; Natalia Gambaryan; Chao Meng; Frederic Perros; Marc Humbert; S. John Wort; Ian M. Adcock
• Keywords: BET inhibitor; CDK inhibitor

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