Redox-sensitve intermediates mediate angiotensin II-induced p38 MAP kinase activation, AP-1 binding activity, and TGF-β expression in adult ventricular cardiomyocytes

Cardiac hypertrophy as an adaptation to increased blood pressure leads to an increase in ventricular expression of tranforming growth factor beta (TGF-beta), probably via the renin-angiotensin system. We studied in vivo to determine whether angiotensin II affects TGF-beta expression independent from mechanical effects caused by the concomitant increase in blood pressure and in vitro intracellular signaling involved in angiotensin II-dependent TGF-beta induction. In vivo, the AT(1) receptor antagonist losartan, but not reduction of blood pressure by hydralazine, inhibited the increase in TGF-beta (1) expression caused by angiotensin II. In vitro, angiotensin II caused an induction of TGF-beta (1) expression in adult ventricular cardiomyocytes and induced AP-1 binding activity. Transfection with "decoys" directed against the binding site of AP-1 binding proteins inhibited the angiotensin II-dependent TGF-beta induction. Angiotensin II induced TGF-beta expression in a p38-MAP kinase-dependent way. p38-MAP kinase activation was diminished in presence of the antioxidants or diphenyleneiodium chloride, or by pretreatment with antisense nucleotides directed against phox22 and nox, components of smooth muscle type NAD( P) H oxidase. Thus, our study identifies a previously unrecognized coupling of cardiac AT receptors to a NAD( P) H oxidase complex similar to that expressed in smooth muscle cells and identifies p38-MAP kinase activation as an important downstream target.