Received for publication January 8, 2008.
Revised March 7, 2008.
Accepted for publication March 10, 2008.

Long-term but not short-term p38MAPK inhibition improves cardiac function and reduces cardiac remodeling post-myocardial infarction

Abstract

p38 Mitogen-activated protein kinase (p38MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38MAPK activity is transiently increased soon after myocardial infarction (MI), suggesting brief inhibition may afford the same benefit as long-term inhibition. We examined chronic 12 week p38MAPK inhibition compared to short term (7 day) then discontinued inhibition post-MI. Post-MI rats at day 7 received either vehicle, RWJ67657 (RWJ; (4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1Himidazol- 2-yl]-3-butyn-1-ol) for 12 weeks (long-term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1 wk-RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 hours post-MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage fractional shortening improved following LT-RWJ and ramipril, but not 1wk-RWJ treatment. Similarly LV contractility, dP/dt _max, was improved (12.5%, 14.4%), and LV end diastolic pressure (LVEDP) was reduced (49.4%, 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and -smooth muscle actin expression in LV non-infarct, border and infarct regions with LT-RWJ and Ram treatment. Hypertrophy was reduced in non-infarct (18.3%, 12.2%) and border regions (16.3%, 12.0%) with both treatments respectively. Animals receiving RWJ 24 hours post-MI for 7 days showed similar improvements in fractional shortening, dP/dt _max, LVEDP, including reduced fibrosis and hypertrophy. In vitro experiments confirmed a dose-dependent reduction in hypertrophy with RWJ following tumor necrosis factor- (TNF) stimulation. Continuous but not short term p38MAPK blockade attenuates post-MI remodeling which is associated with functional benefits on the myocardium.

Key words: Heat Shock Proteins, cardiac function, cardiac remodelling, fibrosis, myocardial infarction, p38 MAPK