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Cardiovascular Research Advance Access [Accepted Manuscript] published online on October 4, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm031
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Regulation of Swelling-Activated Cl- Current by Angiotensin II Signaling and NADPH Oxidase in Rabbit Ventricle

Zuojun Rena, Frank J. Rauccia, David M. Browea,b and Clive M. Baumgartena,c,*

a Department of Physiology and Pauley Heart Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0551
c Department of Internal Medicine (Cardiology) and Biomedical Engineering, and Pauley Heart Center, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0551

* Corresponding author: Clive M. Baumgarten, Ph.D. Dept. of Physiology Medical College of Virginia Virginia Commonwealth University Richmond, VA 23298-0551 Tel: 804-828-4773 Fax: 804-828-7382 E-mail: clive.baumgarten{at}cu.edu

Aims: We assessed whether hypoosmotic swelling of cardiac myocytes activates volume-sensitive Cl– current (ICl,swell) via the angiotensin II (AngII)-reactive oxygen species (ROS) signaling cascade. The AngII-ROS pathway previously was shown to elicit ICl,swell upon mechanical stretch of ß1D integrin. Integrin stretch and osmotic swelling are, however, distinct stimuli. For example, blocking Src kinases stimulates swelling-induced but inhibits stretch-induced ICl,swell.

Methods: ICl,swell was measured in rabbit ventricular myocytes by whole-cell voltage clamp.

Results: Swelling-induced ICl,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 ICl,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 ICl,swell. Ultimately, AngII signals via NADPH oxidase (NOX) and superoxide anion, oO2-. NOX inhibitors, diphenyleneiodonium, apocynin and gp91ds-tat, eliminated ICl,swell, whereas scramb-tat, an inactive gp91ds-tat analogue, was ineffective. oO2- rapidly dismutates to H2O2. Consistent with H2O2 being a downstream effector, catalase inhibited ICl,swell, and exogenous H2O2 overcame suppression of ICl,swell by AT1 receptor, EGFR kinase, and PI-3K blockers.

Conclusions: Activation of ICl,swell by osmotic swelling is controlled by the AngII-ROS cascade, the same pathway previously implicated in ICl,swell activation by integrin stretch. This in part explains why ICl,swell is persistently activated in several models of cardiac disease.

KEYWORDS Cl-channel; Angiotensin; NADPH oxidase; Signal transduction; Stretch/m-e coupling

Time for primary review: 13 days

b D.M. Browe's present address is: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institutes of Health, Baltimore, MD 21224-6825.


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 Cardiovasc ResHome page
S. J. Kim and Y. E. Earm
Journeying down the long and winding road: the whole picture of volume-activated Cl- channel activation in cardiac myocytes
Cardiovasc Res, January 1, 2008; 77(1): 6 - 7.
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