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Selective Pharmacologic Inhibition of Class IIa Histone Deacetylases Rescues Experimental Pulmonary Arterial Hypertension

Jongmin Kim

Cheo Hwongbo

Xiaoyue Hu

Yujong Kang

Irinna Papangeli

Devi Mehrotra

hk park

Danielle McLean

S Comhair

Serpil Erzurum

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Conference: 2014 International PHA Conference and Scientific Sessions

Release Date: 06.22.2014

Presentation Type: Abstracts

File Download: 2014 Conference Abstract - Jongmin Kim

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Background: Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary arterioles, characterized by increased pulmonary arterial pressure and right ventricular failure. The etiology of PAH is complex, but aberrant proliferation of the pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) is thought to play an important role inits pathogenesis. Our recent identification of a key signaling paradigm in PAECs involving apelin, microRNAs (miRNAs) 424 and 503, and FGF2/FGFR1 demonstrate the importance of crosstalk amongthese molecules in maintenance of pulmonary vascular homeostasis.

Methods and Results: We demonstrate that the transcription factor myocyte enhancer factor 2 (MEF2) is a cis-acting factor that regulates miR-424 and miR-503 expression downstream of apelin in PAECs. MEF2 transcriptional activity was found to be significantly decreased in PAH PAECs. This is mediatedby increased nuclear localization of two class IIa histone deacetylases (HDACs) in PAH PAECs, namely HDAC4 and HDAC5, which negatively regulate MEF2 function. Selective pharmacologic inhibition ofclass IIa HDACs led to restoration of MEF2 transcriptional targets and inhibition of PAH PAEC migration and proliferation. More importantly, pharmacologic class IIa HDAC inhibition in two independent experimental models of PAH led to amelioration of the disease, as demonstrated by: 1) significant improvement in the right ventricular systolic pressure, 2) significant reduction in the rightventricular hypertrophy, 3) significant reduction in the pulmonary arteriolar muscularization, and 4) significant decrease in vascular cell proliferation.

Conclusions: These findings demonstrate that restoration of endothelial MEF2 activity, achieved byselective inhibition of class IIa HDACs, is a novel, promising therapeutic strategy in PAH.

Type: Basic Science