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

Abstract

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.Myocardial infarction (MI) results in progressive structural changes to the myocardium that progress to left ventricular (LV) dysfunction. As a compensatory measure to the decrease in cardiac output following MI, angiotensin II (AngII) and norepinephrine are activated to maintain cardiac function. However, long-term activation promotes vasoconstriction and pathological cardiac remodeling, leading to cardiac dysfunction. In addition, the release of proinflammatory cytokines contributes to the pathological process. Post-MI remodeling is characterized by LV dilatation, necrosis, and thinning of the LV wall, infarct expansion, hypertrophy of myocytes in the viable myocardium, and an increased accumulation of extracellular matrix material (fibrosis) within the infarcted and noninfarcted heart, impeding ventricular function (Tzanidis et al., 2001;Remme, 2003;See et al., 2004).Evidence indicates that p38 mitogen-activated protein kinase (p38 MAPK) may be a common intracellular signaling pathway involved in cardiac remodeling, activated by

Role of p38 inhibition in cardiac ischemia/reperfusion injury

“…To date, in vivo studies on the use of p38 inhibitors have been reported with different doses, modes of treatment, duration of treatment, and animal species (Table 3). Many studies have demonstrated the benefit of p38 inhibitors in the in vivo model of sustained ischemia, either in the small animal or large animal model, where p38 inhibitors were found to reduce the infarct size [21,32,68,69] and improve LV function [33,[69][70][71][72][73][74]. Nevertheless, inconsistent reports do exist, mostly from studies performed in the large animal model.…”

“…Chronic studies investigating the long-term (1-14 weeks) effect of p38 inhibitor in ischemia/reperfusion have been reported. Most of these studies demonstrated that long-term treatment with p38 inhibitors following the induction of myocardial infarction had beneficial effects, such as improved cardiac function [33,[70][71][72][73][74]77], inhibited infarct expansion [33], reduced scar size [77], and suppressed myocardial fibrosis [74].…”

Transcriptional control of cardiac fibroblast plasticity

“…TAK1/p38α has been specifically implicated in promoting myofibroblast activation; pharmacological inhibition of p38 blunts TGFβ-dependent Acta2 expression and the development of fibrosis in multiple organs, including the heart [91–94]. TGFβ stimulation of human dermal fibroblasts also triggers ERK phosphorylation and CTGF expression, which contributes to myofibroblast activation and cytoskeletal rearrangements [95, 96].…”

Opposing Effects of Age and Calorie Restriction on Molecular Determinants of Myocardial Ischemic Tolerance

“…3, Table 2). Given evidence that p38-MAPK induces cardiac fibrosis and dysfunction [78][79][80] and mediates detrimental remodeling postischemia, 81,82 enhanced postischemic activation may contribute to age-dependent changes in postischemic remodeling. Clinical and experimental data support adverse remodeling in aged myocardium from humans and animal models.…”