Mk2-deficient mice are bradycardic and display delayed hypertrophic remodeling in response to a chronic increase in afterload

BACKGROUND: Mitogen-activated protein kinase–activated protein kinase-2 (MK2) is a protein serine/threonine kinase activated by p38α/β. Herein, we examine the cardiac phenotype of pan MK2-null (MK2−/−) mice. METHODS AND RESULTS: Survival curves for male MK2+/+ and MK2−/− mice did not differ (Mantel-Cox test, P=0.580). At 12 weeks of age, MK2−/− mice exhibited normal systolic function along with signs of possible early diastolic dysfunction; however, aging was not associated with an abnormal reduction in diastolic function. Both R-R interval and P-R segment durations were prolonged in MK2-deficient mice. However, heart rates normalized when isolated hearts were perfused ex vivo in working mode. Ca2+ transients evoked by field stimulation or caffeine were similar in ventricular myocytes from MK2+/+ and MK2−/− mice. MK2−/− mice had lower body temperature and an age-dependent reduction in body weight. mRNA levels of key metabolic genes, including Ppargc1a, Acadm, Lipe, and Ucp3, were increased in hearts from MK2−/− mice. For equivalent respiration rates, mitochondria from MK2−/− hearts showed a significant decrease in Ca2+ sensitivity to mitochondrial permeability transition pore opening. Eight weeks of pressure overload increased left ventricular mass in MK2+/+ and MK2−/− mice; however, after 2 weeks the increase was significant in MK2+/+ but not MK2−/− mice. Finally, the pressure overload–induced decrease in systolic function was attenuated in MK2−/− mice 2 weeks, but not 8 weeks, after constriction of the transverse aorta. CONCLUSIONS: Collectively, these results implicate MK2 in (1) autonomic regulation of heart rate, (2) cardiac mitochondrial function, and (3) the early stages of myocardial remodeling in response to chronic pressure overload.