Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 316, Issue 1, Pages L35-L44Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00012.2018
Keywords
acute lung injury; Cx40; endothelial permeability; ROCK
Categories
Funding
- National Natural Science Foundation of China [81370001, 81300037, 81000028, 81570031, 81101889, 81472332, 81341006]
- Key Research and Development Program of Jiangsu Province [BE2016714]
- Natural Science Foundation of Jiangsu Province [BK2010333, BK2011481]
- 333 Elitist Training Program, Jiangsu, China [BRA2013135, BRA2017129]
- Six Talent Peaks Training Program, Jiangsu, China [2015-WSN-117, 2014-WSN-078]
- Distinguished Medical Specialist Program, Jiangsu, China
- Innovative and Entrepreneurial Elite Team Program (2016), Jiangsu, China
- Young Medical Talents Training Program, Jiangsu, China [QNRC2016447]
- Zhongshan Hospital [2016ZSLC15]
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Increased pulmonary vascular permeability is a hallmark of acute lung injury (ALI). Connexin 40 (Cx40) is a gap junctional protein abundantly present in the lung microvascular endothelium. Yet, the role of Cx40 in the regulation of lung vascular permeability and its underlying mechanisms are unclear. Here, we tested the hypothesis that Cx40 participates in regulation of lung endothelial permeability via a mechanism involving a Rho-associated protein kinase (ROCK) dependent regulation of myosin light chain (MLC). In murine models of intratracheal acid-or LPS-induced lung injury, genetic deficiency of Cx40 attenuated key features of ALI including vascular barrier failure. In human pulmonary microvascular endothelial cells (PMVECs), thrombin-induced loss of transendothelial electrical resistance was attenuated by a Cx40-inhibiting mimetic peptide ((40)GAP(27)), Cx40-specific shRNA, or ROCK inhibitor Y27632. In isolated perfused mouse lungs, platelet-activating factor-induced lung weight gain was abrogated by gap junction blocker carbenoxolone, (40)GAP(27), Y27632, or genetic deficiency of Cx40. Phosphorylation of MLC20 increased drastically in both LPS-treated PMVECs and HCl-treated mouse lungs. Expression of ROCK1 was increased in both LPS-treated PMVECs and HCl-treated mouse lungs, and paralleled by phosphorylation of MLC20. Coimmunoprecipitation experiments revealed protein-protein interaction between ROCK1 and Cx40. LPS-induced upregulation of ROCK1 and phosphorylation of MLC20 were blocked by knockdown of Cx40. LPS caused phosphorylation of myosin phosphatase targeting subunit 1, which could be abrogated by Y27632 or Cx40-shRNA. Our findings reveal a role of Cx40 in regulation of ROCK1 and MLC20 that contributes critically to lung vascular barrier failure in ALI.
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