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 hypertensive Dahl rats with heart failure (n = 16). The isolated heart from each animal was stretched on a Langendorff apparatus at an equivalent diastolic wall stress, and the p38-MAPK activity of the left ventricular (LV) myocardium was analyzed by immunoprecipitation-kinase assay. Compared to the control hearts, the stretch-induced p38-MAPK activities were significantly decreased, and inversely correlated with the LV diameter (r = -0.73, P < 0.01). Chronic treatment with an angiotensin II AT1-receptor antagonist, valsartan (10 mg/kg/day), ameliorated cardiac function and remodeling process in the failing hearts, which was associated with an improvement of the p38-MAPK activities. Thus, the mechano-signal transduction of p38-MAPK pathway is downregulated in the failing hearts, along with progressive ventricular remodeling. The data also suggest that the beneficial effects of the AT1-receptor antagonists are potentially mediated by the restoration of cardiac growth-related signal transduction.
Yasaka
A
A
Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Hayashida
W
W
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001835:Body Weight; D003971:Diastole; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology*; D006439:Hemodynamics / Q000502:physiology*; D066298:In Vitro Techniques; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000201:enzymology*; D009929:Organ Size; D051381:Rats; D020303:Rats, Inbred Dahl; D012016:Reference Values; D013599:Systole; D013777:Tetrazoles / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D016277:Ventricular Function, Left; D016474:Weight-Bearing; D048051:p38 Mitogen-Activated Protein Kinases
D000959:Antihypertensive Agents; D013777:Tetrazoles; D000068756:Valsartan; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014633:Valine