ClC-3 chloride channel is upregulated by hypertrophy and inflammation in rat and canine pulmonary artery.
Cl- channels have been implicated in essential cellular functions including volume regulation, progression of cell cycle, cell proliferation and contraction, but the physiological functions of the ClC-3 channel are controversial. We tested the hypothesis that the ClC-3 gene (ClCn-3) is upregulated in hypertensive pulmonary arteries of monocrotaline-treated rats, and upregulated ClC-3 channel aids viability of pulmonary artery smooth muscle cells (PASMCs). Experimental pulmonary hypertension was induced in rats by a single subcutaneous administration of monocrotaline (60 mg kg(-1)). Injected animals developed characteristic features of pulmonary hypertension including medial hypertrophy of pulmonary arteries and right ventricular hypertrophy. Reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and Western immunoblot analysis indicated that histopathological alterations were associated with upregulation of the ClC-3 mRNA and protein expression in both smooth muscle cells of hypertensive pulmonary arteries and in cardiac myocytes. RT-PCR analysis of mRNA, extracted from canine cultured PASMCs, indicated that incubation with the inflammatory mediators endothelin-1 (ET-1), platelet-derived growth factor (PDGF), interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNF alpha), but not transforming growth factor beta (TGFbeta), upregulated ClC-3 mRNA. Adenovirus-mediated delivery and overexpression of ClC-3 in canine PASMCs improved cell viability against increasing concentrations of hydrogen peroxide (H2O2, range 50-250 microM). In conclusion, upregulation of ClC-3 in rat hypertensive lung and heart is a novel observation. Our functional data suggest that upregulation of ClC-3 is an adaptive response of inflamed pulmonary artery, which enhances the viability of PASMCs against reactive oxygen species.
Dai
Yan-Ping
YP
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557-0270, USA.
Bongalon
Shaner
S
Hatton
William J
WJ
Hume
Joseph R
JR
Yamboliev
Ilia A
IA
D000818:Animals; D001167:Arteritis / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006973:Hypertension / Q000378:metabolism; D006984:Hypertrophy / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D018118:Chloride Channels; C115376:ClC-3 channel
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