ClC‐3 chloride channel is upregulated by hypertrophy and inflammation in rat and canine pulmonary artery

1 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). 2 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. 3 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. 4 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‐1β) and tumor necrosis factor alpha (TNFα), but not transforming growth factor beta (TGFβ), upregulated ClC‐3 mRNA. 5 Adenovirus‐mediated delivery and overexpression of ClC‐3 in canine PASMCs improved cell viability against increasing concentrations of hydrogen peroxide (H2O2, range 50–250 μM). 6 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. British Journal of Pharmacology (2005) 145, 5–14. doi:10.1038/sj.bjp.0706135