Inactivation of MK2 in mice with acute p38 activation partially reduced cardiomyocyte hypertrophy, improved contractile performance, and prevented early lethality compared to wild-type mice.
MK2 is a crucial downstream mediator of p38-induced pathological cardiac hypertrophy and remodeling, specifically regulating COX-2 protein synthesis.
RATIONALE: Activation of p38 mitogen-activated protein kinase (MAPK) has a significant impact on cardiac gene expression, contractility, extracellular matrix remodeling, and inflammatory response in heart. The p38 kinase pathway also has a controversial role in cardiac hypertrophy. MAPK-activated protein kinase-2 (MK2) is a well-established p38 downstream kinase, yet its contribution to p38-mediated pathological response in heart has not been investigated. OBJECTIVE: We examined the specific contribution of MK2 to the pathological remodeling induced by p38. METHODS AND RESULTS: We used a cardiomyocyte specific and inducible transgenic approach to determine the functional and molecular impact of acute activation of the p38 pathway in heart in either a MK2 wild-type or a MK2-null background. p38 activation in wild-type mice led to a rapid onset of lethal cardiomyopathy associated with cardiomyocyte hypertrophy, interstitial fibrosis, and contractile dysfunction. Inactivation of MK2 partially but significantly reduced cardiomyocyte hypertrophy, improved contractile performance, and prevented early lethality. MK2 inactivation had no effect on the mRNA levels of hypertrophic marker genes or the proinflammatory gene cyclooxygenase (COX)-2. However, MK2 had a major role in COX-2 protein synthesis without affecting the mRNA level or protein stability. CONCLUSIONS: p38 activity in adult myocytes can contribute to pathological hypertrophy and remodeling in adult heart and that MK2 is an important downstream molecule responsible for specific features of p38-induced cardiac pathology.
Streicher et al. (Fri,) conducted a other in Cardiac hypertrophy. MK2 inactivation (MK2-null background) vs. MK2 wild-type background was evaluated on Cardiomyocyte hypertrophy, contractile performance, and early lethality. Inactivation of MK2 in mice with acute p38 activation partially reduced cardiomyocyte hypertrophy, improved contractile performance, and prevented early lethality compared to wild-type mice.