Regulation of swelling-activated Cl(-) current by angiotensin II signalling and NADPH oxidase in rabbit ventricle.

ABSTRACT: We assessed whether hypoosmotic swelling of cardiac myocytes activates volume-sensitive Cl(-) current (I Cl,swell) via the angiotensin II (AngII)-reactive oxygen species (ROS) signalling cascade. The AngII-ROS pathway previously was shown to elicit I(Cl,swell) upon mechanical stretch of beta(1D) integrin. Integrin stretch and osmotic swelling are, however, distinct stimuli. For example, blocking Src kinases stimulates swelling-induced but inhibits stretch-induced I Cl,swell.I Cl,swell was measured in rabbit ventricular myocytes by whole-cell voltage clamp. Swelling-induced I Cl,swell was completely blocked by losartan and eprosartan, AngII type I receptor (AT1) antagonists. AT1 stimulation transactivates epidermal growth factor receptor (EGFR) kinase. Blockade of EGFR kinase with AG1478 abolished both I Cl,swell and AngII-induced Cl(-) current, whereas exogenous EGF evoked a Cl(-) current that was suppressed by osmotic shrinkage. Phosphatidylinositol 3-kinase (PI-3K) is downstream of EGFR kinase, and PI-3K inhibitors LY294002 and wortmannin blocked I Cl,swell. Ultimately, AngII signals via NADPH oxidase (NOX) and superoxide anion, O2*. NOX inhibitors, diphenyleneiodonium, apocynin and gp91ds-tat, eliminated I Cl,swell, whereas scramb-tat, an inactive gp91ds-tat analogue, was ineffective. O2* rapidly dismutates to H2O2. Consistent with H2O2 being a downstream effector, catalase inhibited I Cl,swell, and exogenous H2O2 overcame suppression of I Cl,swell by AT1 receptor, EGFR kinase, and PI-3K blockers. H2O2-induced current was not blocked by osmotic shrinkage, however.Activation of I Cl,swell by osmotic swelling is controlled by the AngII-ROS cascade, the same pathway previously implicated in I Cl,swell activation by integrin stretch. This in part explains why I Cl,swell is persistently activated in several models of cardiac disease.

SUBMITTER: Ren Z 

PROVIDER: S-EPMC2278237 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature