Abstract P188: Suppression of MK2 Signaling Protects Against Pressure Overload-Induced Cardiac Dysfunction
p38 mitogen-activated protein kinases (MAPKs) regulate a broad range of cellular activities but have been implicated in the pathogenesis of cardiovascular diseases. The mechanisms whereby p38 exerts divergent effects are unknown. Current p38 inhibitors both produce serious side effects and loose efficacy with chronic use. Hence, a better understanding of the downstream targets of p38, i.e. MAPK-activated protein kinases (MKs), is essential. We hypothesized that inhibition of MK2 activity (MK2-/-) during chronic pressure overload is cardioprotective. Twelve-week-old MK2-/- and littermate control (MK2+/+) mice were subjected to transverse aortic constriction (2 wks, n=8). MK2-/- mice showed a ∼20% reduced increase in heart weight-to-tibia length ratio (Fig A) despite similar increases in mean blood pressure and ANP expression. Compared to controls, banded MK2-/- hearts also showed preserved left ventricular: (i) fractional shortening, (ii) ejection fraction (preserved at 72.5 ± 2.2% after banding for MK2-/- but decreased from 67.9 ± 3.6% to 58.8 ± 3.4% in MK2+/+, p<0.05, Fig B), and (iii) diastolic function evidenced by the ratio of transmitral and myocardial early diastolic velocities (E/Em preserved after banding in MK2-/- but increased by 78.8 ± 11.1% in MK2+/+, p<0.01). MK2 deficiency did not reduce interstitial fibrosis. For equivalent respiration rates, mitochondria from MK2-/- hearts showed a significant decrease in Ca2+-sensitivity for mitochondrial permeability transition pore opening (p<0.05, Fig C). Overall, these results suggest that MK2 mediates part of the detrimental remodeling evoked by chronic pressure overload-induced activation of p38.
- © 2011 by American Heart Association, Inc.