Role of connexin 43 in vascular hyperpermeability and relationship to Rock1-MLC20 pathway in septic rats.
Connexin (Cx)43 has been shown to participate in several cardiovascular diseases. Increased vascular permeability is a common and severe complication in sepsis or septic shock. Whether or not Cx43 takes part in the regulation of vascular permeability in severe sepsis is not known, and the underlying mechanism has not been described. With cecal ligation and puncture-induced sepsis in rats and lipopolysaccharide (LPS)-treated vascular endothelial cells (VECs) from pulmonary veins, the role of Cx43 in increased vascular permeability and its relationship to the RhoA/Rock1 pathway were studied. It was shown that vascular permeability in the lungs, kidneys, and mesentery in sepsis rats and LPS-stimulated monolayer pulmonary vein VECs was significantly increased and positively correlated with the increased expression of Cx43 and Rock1 in these organs and cultured pulmonary vein VECs. The connexin inhibitor carbenoxolone (10 mg/kg iv) and the Rock1 inhibitor Y-27632 (2 mg/kg iv) alleviated the vascular leakage of lung, mesentery, and kidney in sepsis rats. Overexpressed Cx43 increased the phosphorylation of 20-kDa myosin light chain (MLC20) and the expression of Rock1 and increased the vascular permeability and decreased the transendothelial electrical resistance of pulmonary vein VECs. Cx43 RNA interference decreased the phosphorylation of MLC20 and the expression of Rock1 and decreased LPS-stimulated hyperpermeability of cultured pulmonary vein VECs. The Rock1 inhibitor Y-27632 alleviated LPS- and overexpressed Cx43-induced hyperpermeability of monolayer pulmonary vein VECs. This report shows that Cx43 participates in the regulation of vascular permeability in sepsis and that the mechanism is related to the Rock1-MLC20 phosphorylation pathway.
State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Jie
J
Zhang
State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Guang-Ming
GM
Yang
State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Yu
Y
Zhu
State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Xiao-Yong
XY
Peng
State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
Tao
T
Li
State Key Laboratory of Trauma, Burns, and Combined Injury, Second Department of Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China liangmingliu@yahoo.com.
Liang-Ming
LM
Liu
D000818:Animals; D002199:Capillary Permeability; D002432:Cecum / Q000473:pathology; D018031:Connexin 43 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000097:blood; D007668:Kidney / Q000098:blood supply; D016086:Lentivirus / Q000378:metabolism; D008026:Ligation; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply; D008297:Male; D008643:Mesentery / Q000098:blood supply; D008970:Molecular Weight; D018994:Myosin Light Chains / Q000276:immunology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011667:Pulmonary Veins / Q000473:pathology; D011677:Punctures; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology*; D015398:Signal Transduction; D022502:Stress Fibers / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D018031:Connexin 43; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018994:Myosin Light Chains; D014409:Tumor Necrosis Factor-alpha; C578418:ROCK1 protein, rat; D054460:rho-Associated Kinases; D011493:Protein Kinase C; D020742:rhoA GTP-Binding Protein
MLC20; RhoA/Rock1 pathway; connexin 43; sepsis; vascular permeability