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Restoration of Impaired Endothelial MEF2 Function Rescues Pulmonary Arterial Hypertension.
MedLine Citation:
PMID:  25336633     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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 in its pathogenesis. Understanding the mechanisms of transcriptional gene regulation involved in pulmonary vascular homeostasis can provide key insights into potential therapeutic strategies.
METHODS AND RESULTS: -We demonstrate that the activity of the transcription factor myocyte enhancer factor 2 (MEF2) is significantly impaired in the PAECs derived from subjects with PAH. We identified MEF2 as the key cis-acting factor that regulates expression of a number of transcriptional targets involved in pulmonary vascular homeostasis, including microRNAs 424 and 503, connexins 37, connexin 40, Krűppel Like Factor 2 (KLF2) and KLF4, which were found to be significantly decreased in PAH PAECs. The impaired MEF2 activity in PAH PAECs was mediated by excess nuclear accumulation of two class IIa histone deacetylases (HDACs) that inhibit its function, namely HDAC4 and HDAC5. Selective, pharmacologic inhibition of class IIa HDACs led to restoration of MEF2 activity in PAECs, as demonstrated by increased expression of its transcriptional targets, decreased cell migration and proliferation, and rescue of experimental pulmonary hypertension (PH) models.
CONCLUSIONS: -Our results demonstrate that strategies to augment MEF2 activity holds potential therapeutic value in PAH. Moreover, we identify selective HDAC IIa inhibition as a viable alternative approach to avoid the potential adverse effects of broad spectrum HDAC inhibition in PAH.
Authors:
Jongmin Kim; Cheol Hwangbo; Xiaoyue Hu; Yujung Kang; Irinna Papangeli; Devi Mehrotra; Hyekyung Park; Danielle L McLean; Hyekyung Ju; Suzy A Comhair; Serpil C Erzurum; Hyung J Chun
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-21
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-22     Completed Date:  -     Revised Date:  2014-10-23    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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