p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction.
Stress is gaining increasing acceptance as an independent risk factor contributing to adverse cardiovascular outcomes. Potential mechanisms responsible for the deleterious effects of stress on the development and progression of cardiovascular disease remain to be elucidated. An established animal model of stress in humans is the prenatally stressed (PS) rat. We stressed rats in their third trimester of pregnancy by daily injections of saline and moving from cage to cage. Male offspring of these stressed dams (PS) and age-matched male control offspring (control) were further subjected to restraint stress (R) at 6 and 7 wk of age. Echocardiography revealed a significant decrease in fractional shortening in PS + R vs. controls + R (45.8 +/- 3.9 vs. 61.9 +/- 2.4%, PS + R vs. controls + R; P < 0.01; n = 12). Isolated adult rat ventricular myocytes from PS + R also revealed diminished fractional shortening (6.7 +/- 0.8 vs. 12.7 +/- 1.1%, PS + R vs. controls + R; P < 0.01; n = 24) and blunted inotropic responses to isoproterenol (P < 0.01; n = 24) determined by automated border detection. The p38 mitogen-activated protein (MAP) kinase inhibitor SB-203580 blocked p38 MAP kinase phosphorylation, reversed the depression in fractional shortening, and partially ameliorated the blunted adrenergic signaling seen in adult rat ventricular myocytes from PS + R. Phosphorylation of p38 MAP kinase in cardiac myocytes by stress may be sufficient to lead to myocardial dysfunction in animal models and possibly humans.
Dept. of Medicine, WVU Cardiology, West Virginia University School of Medicine, Medical Center Drive, Morgantown, WV 26506-9157, USA.
Hong
H
Kan
Dale
D
Birkle
Abnash C
AC
Jain
Conard
C
Failinger
Sherry
S
Xie
Mitchell S
MS
Finkel
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D009200:Myocardial Contraction; D011725:Pyridines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000150:complications / Q000503:physiopathology*; D016896:Treatment Outcome; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D007093:Imidazoles; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580