Megakaryocytic leukemia 1 (MKL1) regulates hypoxia induced pulmonary hypertension in rats

PLoS One. 2014 Mar 19;9(3):e83895. doi: 10.1371/journal.pone.0083895. eCollection 2014.

Abstract

Hypoxia induced pulmonary hypertension (HPH) represents a complex pathology that involves active vascular remodeling, loss of vascular tone, enhanced pulmonary inflammation, and increased deposition of extracellular matrix proteins. Megakaryocytic leukemia 1 (MKL1) is a transcriptional regulator known to influence cellular response to stress signals in the vasculature. We report here that in response to chronic hypobaric hypoxia, MKL1 expression was up-regulated in the lungs in rats. Short hairpin RNA (shRNA) mediated depletion of MKL1 significantly ameliorated the elevation of pulmonary arterial pressure in vivo with a marked alleviation of vascular remodeling. MKL1 silencing also restored the expression of NO, a key vasoactive molecule necessary for the maintenance of vascular tone. In addition, hypoxia induced pulmonary inflammation was dampened in the absence of MKL1 as evidenced by normalized levels of pro-inflammatory cytokines and chemokines as well as reduced infiltration of pro-inflammatory immune cells in the lungs. Of note, MKL1 knockdown attenuated fibrogenesis in the lungs as indicated by picrosirius red staining. Finally, we demonstrate that MKL1 mediated transcriptional activation of type I collagen genes in smooth muscle cells under hypoxic conditions. In conclusion, we data highlight a previously unidentified role for MKL1 in the pathogenesis of HPH and as such lay down groundwork for future investigation and drug development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Cytokines / biosynthesis
  • Gene Expression Regulation
  • Hypertension, Pulmonary / etiology
  • Hypertension, Pulmonary / genetics*
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / complications
  • Hypoxia / genetics*
  • Hypoxia / physiopathology
  • Male
  • Myocytes, Smooth Muscle / metabolism
  • Myocytes, Smooth Muscle / pathology
  • Pulmonary Artery / metabolism*
  • Pulmonary Artery / physiopathology
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Vascular Resistance

Substances

  • Collagen Type I
  • Cytokines
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factors
  • myocardin-related transcription factor-A, rat

Grants and funding

This study was supported, in part, by the National Basic Science Research “973” Program of China (2012CB518201, 2012CB517503), the Program for New Century Excellent Talents in University of China (NCET-11-0991), Natural Science Foundation of China (81100041, 31270805), Natural Science Foundation of Jiangsu Province (BK2012043), the Ministry of Education (212059), and the Postdoctoral Research Grant of China (20100471771). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.