Arizona Health Sciences

MAPK-activated protein kinase-2 in cardiac hypertrophy and cyclooxygenase-2 regulation in heart.

TitleMAPK-activated protein kinase-2 in cardiac hypertrophy and cyclooxygenase-2 regulation in heart.
Publication TypeJournal Article
Year of Publication2010
AuthorsStreicher JM, Ren S, Herschman H, Wang Y
JournalCirc Res
Volume106
Issue8
Pagination1434-43
Date Published2010 Apr 30
ISSN1524-4571
KeywordsAnimals, Cardiomegaly, Cells, Cultured, Cyclooxygenase 2, Disease Models, Animal, Enzyme Activation, Enzyme Stability, Female, Fibrosis, Gene Expression Regulation, Heart Failure, Intracellular Signaling Peptides and Proteins, Male, MAP Kinase Kinase 3, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myocardial Contraction, Myocytes, Cardiac, p38 Mitogen-Activated Protein Kinases, Protein-Serine-Threonine Kinases, Rats, Rats, Sprague-Dawley, RNA, Messenger, Signal Transduction, Time Factors, Transfection, Ventricular Remodeling
Abstract

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.

DOI10.1161/CIRCRESAHA.109.213199
Alternate JournalCirc. Res.
PubMed ID20339119
PubMed Central IDPMC2903446
Grant ListR01 HL108186 / HL / NHLBI NIH HHS / United States
R01 CA084572 / CA / NCI NIH HHS / United States
HL088640 / HL / NHLBI NIH HHS / United States
HL080111 / HL / NHLBI NIH HHS / United States
P01 HL080111 / HL / NHLBI NIH HHS / United States
R01 HL103205 / HL / NHLBI NIH HHS / United States
R01 HL088640 / HL / NHLBI NIH HHS / United States
HL70079 / HL / NHLBI NIH HHS / United States
P01 HL080111-050003 / HL / NHLBI NIH HHS / United States
R01 HL070079-08 / HL / NHLBI NIH HHS / United States
R01 HL070079 / HL / NHLBI NIH HHS / United States
R01 HL062311 / HL / NHLBI NIH HHS / United States
R01 HL062311-09 / HL / NHLBI NIH HHS / United States
CA084572 / CA / NCI NIH HHS / United States
Faculty Member Reference: 
John M. Streicher, PhD