MAPK-Activated Protein Kinase-2 in Cardiac Hypertrophy and Cyclooxygenase-2 Regulation in Heart

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.

[1]  Yibin Wang,et al.  Compensatory hypertrophy induced by ventricular cardiomyocyte-specific COX-2 expression in mice. , 2010, Journal of molecular and cellular cardiology.

[2]  Y. Pinto,et al.  Avoidance of Transient Cardiomyopathy in Cardiomyocyte-Targeted Tamoxifen-Induced MerCreMer Gene Deletion Models , 2009, Circulation research.

[3]  M. Gheorghiade,et al.  Acute heart failure syndromes , 2009, Journal of the American College of Cardiology.

[4]  David R. Anderson,et al.  Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). , 2007, Journal of medicinal chemistry.

[5]  Jayoung Choi,et al.  A novel mitochondrial matrix serine/threonine protein phosphatase regulates the mitochondria permeability transition pore and is essential for cellular survival and development. , 2007, Genes & development.

[6]  S. Horvath,et al.  Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation. , 2006, Physiological genomics.

[7]  Matthew Brook,et al.  Edinburgh Research Explorer Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element , 2022 .

[8]  L. Cupples,et al.  The relationship between aldosterone, oxidative stress, and inflammation in chronic, stable human heart failure. , 2006, Journal of cardiac failure.

[9]  F. B. Engel,et al.  Cardiomyocyte Proliferation: A Platform for Mammalian Cardiac Repair , 2005, Cell cycle.

[10]  W. Seeger,et al.  Mechanisms of Cardiac Depression Caused by Lipoteichoic Acids From Staphylococcus aureus in Isolated Rat Hearts , 2005, Circulation.

[11]  D. Kass,et al.  p38 MAP Kinase Mediates Inflammatory Cytokine Induction in Cardiomyocytes and Extracellular Matrix Remodeling in Heart , 2005, Circulation.

[12]  R. Bolli,et al.  Overexpression of Mitogen-activated Protein Kinase Kinase 6 in the Heart Improves Functional Recovery from Ischemia in Vitro and Protects against Myocardial Infarction in Vivo* , 2005, Journal of Biological Chemistry.

[13]  J. Miyazaki,et al.  Mitogen-Activated Protein Kinase Plays a Critical Role in Cardiomyocyte Survival but Not in Cardiac Hypertrophic Growth in Response to Pressure Overload , 2004 .

[14]  T. Huynh,et al.  Inhibition of COX pathway in experimental myocardial infarction. , 2004, Journal of molecular and cellular cardiology.

[15]  M. Mendez,et al.  Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse. , 2004, American journal of physiology. Heart and circulatory physiology.

[16]  G. Biondi-Zoccai,et al.  Cyclo-oxygenase-2 (COX-2) expression at the site of recent myocardial infarction: friend or foe? , 2004, Heart.

[17]  Andrew J. Dannenberg,et al.  Regulation of Cyclooxgenase-2 mRNA Stability by Taxanes , 2003, Journal of Biological Chemistry.

[18]  P. Anderson,et al.  Regulation of Cyclooxygenase-2 Expression by the Translational Silencer TIA-1 , 2003, The Journal of experimental medicine.

[19]  Bruce Tidor,et al.  Proteomic Identification of 14-3-3ζ as a Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 Substrate: Role in Dimer Formation and Ligand Binding , 2003, Molecular and Cellular Biology.

[20]  Timothy E Hewett,et al.  Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. , 2003, The Journal of clinical investigation.

[21]  J. Molkentin,et al.  Temporal activation of c‐Jun N‐terminal kinase in adult transgenic heart via cre‐loxP‐mediated DNA recombination , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  Attila Kovacs,et al.  The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. , 2003, The Journal of clinical investigation.

[23]  P. Cohen,et al.  Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP‐K2 and its interaction with cytokine mRNAs , 2002, The EMBO journal.

[24]  M. Gaestel,et al.  Distinct Cellular Functions of MK2 , 2002, Molecular and Cellular Biology.

[25]  Heping Cheng,et al.  Cellular Mechanisms of p 38 MAPK – Induced Negative Inotropic Effect : Suppression of Myofilament Ca , 2002 .

[26]  G. Kollias,et al.  MK2 Targets AU-rich Elements and Regulates Biosynthesis of Tumor Necrosis Factor and Interleukin-6 Independently at Different Post-transcriptional Levels* , 2002, The Journal of Biological Chemistry.

[27]  D. Kass,et al.  The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  M. Crackower,et al.  Temporally Regulated and Tissue-Specific Gene Manipulations in the Adult and Embryonic Heart Using a Tamoxifen-Inducible Cre Protein , 2001, Circulation research.

[29]  W. Seeger,et al.  Endotoxin-Induced Myocardial Tumor Necrosis Factor-&agr; Synthesis Depresses Contractility of Isolated Rat Hearts: Evidence for a Role of Sphingosine and Cyclooxygenase-2–Derived Thromboxane Production , 2000, Circulation.

[30]  Gary Brewer,et al.  Regulation of Cyclooxygenase 2 mRNA Stability by the Mitogen-Activated Protein Kinase p38 Signaling Cascade , 2000, Molecular and Cellular Biology.

[31]  P. Douglas,et al.  Transgenic expression of green fluorescence protein can cause dilated cardiomyopathy , 2000, Nature Medicine.

[32]  R. Kraft,et al.  MAPKAP Kinase 2 Phosphorylates Serum Response Factor in Vitro and in Vivo* , 1999, The Journal of Biological Chemistry.

[33]  J Ross,et al.  Cardiac Muscle Cell Hypertrophy and Apoptosis Induced by Distinct Members of the p38 Mitogen-activated Protein Kinase Family* , 1998, The Journal of Biological Chemistry.

[34]  D. Zechner,et al.  A Role for the p38 Mitogen-activated Protein Kinase Pathway in Myocardial Cell Growth, Sarcomeric Organization, and Cardiac-specific Gene Expression , 1997, The Journal of cell biology.

[35]  Philip R. Cohen,et al.  FGF and stress regulate CREB and ATF‐1 via a pathway involving p38 MAP kinase and MAPKAP kinase‐2. , 1996, The EMBO journal.

[36]  M. Gaestel,et al.  Constitutive Activation of Mitogen-activated Protein Kinase-activated Protein Kinase 2 by Mutation of Phosphorylation Sites and an A-helix Motif (*) , 1995, The Journal of Biological Chemistry.

[37]  W. Garvey.  Modified elastic tissue-Masson trichrome stain. , 1984, Stain technology.

[38]  J. Streicher,et al.  The role of COX-2 in heart pathology. , 2008, Cardiovascular & hematological agents in medicinal chemistry.

[39]  N. Maulik,et al.  MK2-/- gene knockout mouse hearts carry anti-apoptotic signal and are resistant to ischemia reperfusion injury. , 2005, Journal of molecular and cellular cardiology.

[40]  Jiahuai Han,et al.  The p38 signal transduction pathway: activation and function. , 2000, Cellular signalling.

[41]  M. Gaestel,et al.  MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. , 1999, Nature cell biology.

[42]  J. Revel,et al.  Turnover and phosphorylation dynamics of connexin43 gap junction protein in cultured cardiac myocytes. , 1991, The Biochemical journal.