title: Megakaryocytic leukemia 1 (MKL1) regulates hypoxia induced pulmonary hypertension in rats.
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.
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, Ministry of Education, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Zhibin
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, Ministry of Education, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, Ministry of Education, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, Ministry of Education, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Xia
authors.affiliation: Key Laboratory of Cardiovascular Disease, Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, Ministry of Education, Third Military Medical University, Chongqing, China; Key Laboratory of High Altitude Medicine, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014655:Vascular Resistance
chemical_list: D024042:Collagen Type I; D016207:Cytokines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; C557977:myocardin-related transcription factor-A, rat