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Address correspondence to Clive M. Baumgarten, Department of Physiology, Medical College of Virginia, Box 980551, Richmond, VA 23298-0551. Fax: (804) 828-7382; email: clive.baumgarten{at}vcu.edu
Direct stretch of ß1 integrin activates an outwardly rectifying, tamoxifen-sensitive Cl– current (Cl– SAC) via focal adhesion kinase (FAK) and/or Src. The characteristics of Cl– SAC resemble those of the volume-sensitive Cl– current, ICl,swell. Because myocyte stretch releases angiotensin II (AngII), which binds AT1 receptors (AT1R) and stimulates FAK and Src in an autocrine-paracrine loop, we tested whether AT1R and their downstream signaling cascade participate in mechanotransduction. Paramagnetic beads coated with mAb for ß1-integrin were applied to myocytes and pulled upward with an electromagnet while recording whole-cell anion current. Losartan (5 µM), an AT1R competitive antagonist, blocked Cl– SAC but did not significantly alter the background Cl– current in the absence of integrin stretch. AT1R signaling is mediated largely by H2O2 produced from superoxide generated by sarcolemmal NADPH oxidase. Diphenyleneiodonium (DPI, 60 µM), a potent NADPH oxidase inhibitor, rapidly and completely blocked both Cl– SAC elicited by stretch and the background Cl– current. A structurally unrelated NADPH oxidase inhibitor, 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF, 0.5 and 2 mM), also rapidly and completely blocked Cl– SAC as well as a large fraction of the background Cl– current. With continuing integrin stretch, Cl– SAC recovered upon washout of AEBSF (2 mM). In the absence of stretch, exogenous AngII (5 nM) activated an outwardly rectifying Cl– current that was rapidly and completely blocked by DPI (60 µM). Moreover, exogenous H2O2 (10, 100, and 500 µM), the eventual product of NADPH oxidase activity, also activated Cl– SAC in the absence of stretch, whereas catalase (1,000 U/ml), an H2O2 scavenger, attenuated the response to stretch. Application of H2O2 during NADPH oxidase inhibition by either DPI (60 µM) or AEBSF (0.5 mM) did not fully reactivate Cl– SAC, however. These results suggest that stretch of ß1-integrin in cardiac myocytes elicits Cl– SAC by activating AT1R and NADPH oxidase and, thereby, producing reactive oxygen species. In addition, NADPH oxidase may be intimately coupled to the channel responsible for Cl– SAC, providing a second regulatory pathway.
Key Words: stretch-activated channels • swelling-activated channels • arrhythmia • preconditioning • heart failure
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