Alterations of load-induced p38 MAP kinase activation in failing rat hearts

Hemodynamic load-induced cardiac p38 mitogen-activated protein kinase (MAPK ) activation was studied in normotensive control Dahl rats (n = 10) and hyp ertensive Dahl rats with heart failure (n = 16). The isolated heart from ea ch animal was stretched on a Langendorff apparatus at an equivalent diastol ic wall stress, and the p38-MAPK activity of the left ventricular (LV) myoc ardium was analyzed by immunoprecipitation-kinase assay. Compared to the co ntrol hearts, the stretch-induced p38-MAPK activities were significantly de creased, and inversely correlated with the LV diameter (r = -0.73, P < 0.01 ), Chronic treatment with an angiotensin II AT1-receptor antagonist, valsar tan (10 mg/kg/day), ameliorated cardiac function and remodeling process in the failing hearts, which was associated with an improvement of the p38-MAP K activities. Thus, the mechano-signal transduction of p38-MAPK pathway is downregulated in the failing hearts, along with progressive ventricular rem odeling. The data also suggest that the beneficial effects of the AT1-recep tor antagonists are potentially mediated by the restoration of cardiac grow th-related signal transduction. (C) 2001 Academic Press.