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CARDIOVASCULAR

Long-Term but Not Short-Term p38 Mitogen-Activated Protein Kinase Inhibition Improves Cardiac Function and Reduces Cardiac Remodeling Post-Myocardial Infarction

Departments of Medicine and Epidemiology and Preventive Medicine, National Health and Medical Research Council Centre of Clinical Research Excellence in Therapeutics, Alfred Hospital, Central and Eastern Clinical School, Monash University, Prahran, Victoria, Australia (A.R.K., F.S., D.A.L., A.A., D.M.C., B.H.W., H.K.); and Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia (A.R.K.)

p38 mitogen-activated protein kinase (p38 MAPK) inhibition exerts beneficial effects on left ventricular (LV) remodeling and dysfunction. p38 MAPK 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 p38 MAPK inhibition compared with short-term (7-day) inhibition, and then we discontinued inhibition after MI. Post-MI rats at day 7 received either vehicle, 4-[4-(4-fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol (RWJ67657; RWJ) for 12 weeks (long term; LT-RWJ), RWJ for 1 week and discontinued for 11 weeks (1-week RWJ), or continuous ramipril for 12 weeks. In separate groups of animals, 24 h after MI, vehicle or RWJ was administered for 7 days. Cardiac function was assessed by echocardiography and hemodynamic measurements. Percentage of fractional shortening improved after LT-RWJ and ramipril, but not after 1-week RWJ treatment. Likewise, LV contractility and maximal first derivative of left ventricular pressure (dP/dt_max) was improved (12.5 and 14.4%) and LV end diastolic pressure (LVEDP) was reduced (49.4 and 54.6%) with both treatments. Functional outcomes were accompanied by regression of interstitial collagen I and -smooth muscle actin expression in LV noninfarct, border, and infarct regions with LT-RWJ and ramipril treatment. Hypertrophy was reduced in noninfarct (18.3 and 12.2%) and border regions (16.3 and 12.0%) with both treatments, respectively. Animals receiving RWJ 24 h after 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- stimulation. Continuous but not short-term p38 MAPK blockade attenuates post-MI remodeling, which is associated with functional benefits on the myocardium.

Address correspondence to: Dr. Henry Krum, Department of Epidemiology and Preventive Medicine, Alfred Hospital, Central and Eastern Clinical School, Monash University, Commercial Rd., Prahran, Victoria, Australia 3181. E-mail: henry.krum{at}med.monash.edu.au