MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets.

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

[1]  R. Tiwari,et al.  Macrophages: An elusive yet emerging therapeutic target of atherosclerosis , 2008, Medicinal research reviews.

[2]  Rong Wang,et al.  p38 Mitogen-Activated Protein Kinase Inhibition Decreases TNFalpha Secretion and Protects Against Left Ventricular Remodeling in Rats with Myocardial Ischemia , 2008, Inflammation.

[3]  P. Marin,et al.  GPCR-jacking: from a new route in RTK signalling to a new concept in GPCR activation. , 2007, Trends in pharmacological sciences.

[4]  J. Epstein,et al.  NF1 Regulates a Ras-Dependent Vascular Smooth Muscle Proliferative Injury Response , 2007, Circulation.

[5]  Yibin Wang.  Mitogen-activated protein kinases in heart development and diseases. , 2007, Circulation.

[6]  S. Meloche,et al.  Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo , 2007, Proceedings of the National Academy of Sciences.

[7]  A. Galloway,et al.  Vascular injury and modulation of MAPKs: a targeted approach to therapy of restenosis. , 2007, Cellular signalling.

[8]  J. Schneider,et al.  Grb2 Is Required for Atherosclerotic Lesion Formation , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[9]  Wei Chen,et al.  Differential regulation and properties of MAPKs , 2007, Oncogene.

[10]  D. Morrison,et al.  Integrating signals from RTKs to ERK/MAPK , 2007, Oncogene.

[11]  S. Cook,et al.  The duration of ERK1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1. , 2007, Cellular signalling.

[12]  C. Angermann,et al.  Role of p38 mitogen‐activated protein kinase in cardiac remodelling , 2007, British journal of pharmacology.

[13]  Anthony J. Muslin,et al.  The 14-3-3τ Phosphoserine-Binding Protein Is Required for Cardiomyocyte Survival , 2006, Molecular and Cellular Biology.

[14]  J. Schneider,et al.  ATM-dependent suppression of stress signaling reduces vascular disease in metabolic syndrome. , 2006, Cell metabolism.

[15]  Richard T. Lee,et al.  FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction , 2006, Proceedings of the National Academy of Sciences.

[16]  A. Whitmarsh.  The JIP family of MAPK scaffold proteins. , 2006, Biochemical Society transactions.

[17]  Y. Soini,et al.  p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti‐apoptotic mechanisms , 2006 .

[18]  Mark A Sussman,et al.  Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy , 2006, Proceedings of the National Academy of Sciences.

[19]  J. Molkentin,et al.  Regulation of cardiac hypertrophy by intracellular signalling pathways , 2006, Nature Reviews Molecular Cell Biology.

[20]  W. Pu,et al.  Dilated cardiomyopathy resulting from high-level myocardial expression of Cre-recombinase. , 2006, Journal of cardiac failure.

[21]  H. Rockman,et al.  JNK1 is required to preserve cardiac function in the early response to pressure overload. , 2006, Biochemical and biophysical research communications.

[22]  S. Hazen,et al.  A CD36‐dependent signaling cascade is necessary for macrophage foam cell formation , 2006, Cell metabolism.

[23]  T. Kita,et al.  Activation of TGF-β1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats , 2006 .

[24]  Anthony J. Muslin.  Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. , 2005, Trends in cardiovascular medicine.

[25]  C. Proud,et al.  Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). , 2005, The Biochemical journal.

[26]  C. Liang,et al.  Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits. , 2005, Biochimica et biophysica acta.

[27]  Yibin Wang,et al.  p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. , 2005, Genes & development.

[28]  Paul Tempst,et al.  Phosphorylation and Functional Inactivation of TSC2 by Erk Implications for Tuberous Sclerosisand Cancer Pathogenesis , 2005, Cell.

[29]  Jie Ren,et al.  Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. , 2005, Journal of molecular and cellular cardiology.

[30]  S. Sankey,et al.  Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction. , 2005, Journal of cardiac failure.

[31]  J. Miyazaki,et al.  p38α Mitogen-Activated Protein Kinase Plays a Critical Role in Cardiomyocyte Survival but Not in Cardiac Hypertrophic Growth in Response to Pressure Overload , 2004, Molecular and Cellular Biology.

[32]  G. Sumara,et al.  Requirement of JNK2 for Scavenger Receptor A-Mediated Foam Cell Formation in Atherogenesis , 2004, Science.

[33]  A. Rivard,et al.  Inhibition of Vascular Smooth Muscle Cell Proliferation and Neointimal Formation in Injured Arteries by a Novel, Oral Mitogen-Activated Protein Kinase/Extracellular Signal–Regulated Kinase Inhibitor , 2004, Circulation.

[34]  M. Nieminen,et al.  Regression of electrocardiographic left ventricular hypertrophy during antihypertensive treatment and the prediction of major cardiovascular events. , 2004, JAMA.

[35]  Richard Marais,et al.  The RAF proteins take centre stage , 2004, Nature Reviews Molecular Cell Biology.

[36]  H. Krum,et al.  p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. , 2004, Journal of the American College of Cardiology.

[37]  J. Miyazaki,et al.  Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. , 2004, The Journal of clinical investigation.

[38]  Anthony J. Muslin,et al.  Raf-1 Kinase Is Required for Cardiac Hypertrophy and Cardiomyocyte Survival in Response to Pressure Overload , 2004, Circulation.

[39]  P. Doevendans,et al.  Targeted Inhibition of p38 Mitogen-activated Protein Kinase Antagonizes Cardiac Injury and Cell Death Following Ischemia-Reperfusion in Vivo* , 2004, Journal of Biological Chemistry.

[40]  D. Rosenbaum,et al.  Targeted Activation of c-Jun N-terminal Kinase in Vivo Induces Restrictive Cardiomyopathy and Conduction Defects*[boxs] , 2004, Journal of Biological Chemistry.

[41]  R. Schüle,et al.  Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes , 2004, Molecular and Cellular Biology.

[42]  M. Hori,et al.  Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  D. Morrison,et al.  Regulation of MAP kinase signaling modules by scaffold proteins in mammals. , 2003, Annual review of cell and developmental biology.

[44]  Anthony J. Muslin,et al.  Grb2 Is Required for the Development of Neointima in Response to Vascular Injury , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[45]  C. Kuan,et al.  c‐Jun N‐terminal kinases (JNK) antagonize cardiac growth through cross‐talk with calcineurin–NFAT signaling , 2003, The EMBO journal.

[46]  R. Wetzker,et al.  Transactivation joins multiple tracks to the ERK/MAPK cascade , 2003, Nature Reviews Molecular Cell Biology.

[47]  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.

[48]  M. Hori,et al.  Long-Acting Ca2+ Blockers Prevent Myocardial Remodeling Induced by Chronic NO Inhibition in Rats , 2003, Hypertension.

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

[50]  C. Proud,et al.  Ras/Erk Signaling Is Essential for Activation of Protein Synthesis by Gq Protein-Coupled Receptor Agonists in Adult Cardiomyocytes , 2002, Circulation research.

[51]  Jiahuai Han,et al.  Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL , 2002, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[52]  W. Kolch,et al.  Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases. , 2002, Journal of cell science.

[53]  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.

[54]  Shokei Kim,et al.  Activation of mitogen-activated protein kinases in the non-ischemic myocardium of an acute myocardial infarction in rats. , 2001, Japanese circulation journal.

[55]  Y. Kaneda,et al.  Gene Transfer of Dominant-Negative Mutants of Extracellular Signal-Regulated Kinase and c-Jun NH2-Terminal Kinase Prevents Neointimal Formation in Balloon-Injured Rat Artery , 2001, Circulation research.

[56]  W. Koch,et al.  Cardiac Overexpression of a Gq Inhibitor Blocks Induction of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Activity in In Vivo Pressure Overload , 2001, Circulation.

[57]  Christopher K. Glass,et al.  Atherosclerosis The Road Ahead , 2001, Cell.

[58]  R. Hajjar,et al.  Differential Activation of Signal Transduction Pathways in Human Hearts With Hypertrophy Versus Advanced Heart Failure , 2001, Circulation.

[59]  A. Matsumori,et al.  Role of p38 Mitogen-Activated Protein Kinase in Neointimal Hyperplasia After Vascular Injury , 2000, Arteriosclerosis, thrombosis, and vascular biology.

[60]  R. Kitsis,et al.  The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice , 2000, The EMBO journal.

[61]  John C. Lee,et al.  Extracellular Signal-regulated Kinase Plays an Essential Role in Hypertrophic Agonists, Endothelin-1 and Phenylephrine-induced Cardiomyocyte Hypertrophy* , 2000, The Journal of Biological Chemistry.

[62]  Roy L. Silverstein,et al.  CD36 and atherosclerosis , 2000, Current opinion in lipidology.

[63]  Hiroyuki Tsutsui,et al.  Treatment With Dimethylthiourea Prevents Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction in Mice: Role of Oxidative Stress , 2000, Circulation research.

[64]  Mark A Sussman,et al.  Phosphorylation of elk-1 by MEK/ERK pathway is necessary for c-fos gene activation during cardiac myocyte hypertrophy. , 2000, Journal of molecular and cellular cardiology.

[65]  Anthony J. Muslin,et al.  14‐3‐3 proteins block apoptosis and differentially regulate MAPK cascades , 2000, The EMBO journal.

[66]  F. Urano,et al.  Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. , 2000, Science.

[67]  K. Williams,et al.  Atherosclerosis--an inflammatory disease. , 1999, The New England journal of medicine.

[68]  T. Tsuruo,et al.  ASK1 mediates apoptotic cell death induced by genotoxic stress , 1999, Oncogene.

[69]  K. Tanaka,et al.  Induction of Ets‐1 in endothelial cells during reendothelialization after denuding injury , 1998, Journal of cellular physiology.

[70]  Kohei Miyazono,et al.  Mammalian thioredoxin is a direct inhibitor of apoptosis signal‐regulating kinase (ASK) 1 , 1998, The EMBO journal.

[71]  J. Schrader,et al.  Human Mitogen-activated Protein Kinase Kinase 7 (MKK7) Is a Highly Conserved c-Jun N-terminal Kinase/Stress-activated Protein Kinase (JNK/SAPK) Activated by Environmental Stresses and Physiological Stimuli* , 1998, The Journal of Biological Chemistry.

[72]  N. Olson,et al.  Cell replication in the arterial wall: activation of signaling pathway following in vivo injury. , 1998, Circulation research.

[73]  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.

[74]  D. Bar-Sagi,et al.  Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. , 1998, Science.

[75]  L. Cheng,et al.  Activation of mitogen-activated protein kinases (ERK/JNK) and AP-1 transcription factor in rat carotid arteries after balloon injury. , 1997, Arteriosclerosis, thrombosis, and vascular biology.

[76]  G. Johnson,et al.  Cloning of a Novel Mitogen-activated Protein Kinase Kinase Kinase, MEKK4, That Selectively Regulates the c-Jun Amino Terminal Kinase Pathway* , 1997, The Journal of Biological Chemistry.

[77]  H. Ellinger-Ziegelbauer,et al.  Direct Activation of the Stress-activated Protein Kinase (SAPK) and Extracellular Signal-regulated Protein Kinase (ERK) Pathways by an Inducible Mitogen-activated Protein Kinase/ERK Kinase Kinase 3 (MEKK) Derivative* , 1997, The Journal of Biological Chemistry.

[78]  Minoru Takagi,et al.  Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling Pathways , 1997, Science.

[79]  K. Diener,et al.  Molecular Cloning and Characterization of a Novel Protein Kinase with a Catalytic Domain Homologous to Mitogen-activated Protein Kinase Kinase Kinase* , 1996, The Journal of Biological Chemistry.

[80]  J. Woodgett,et al.  MLK‐3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. , 1996, The EMBO journal.

[81]  M. Karin,et al.  Three distinct signalling responses by murine fibroblasts to genotoxic stress , 1996, Nature.

[82]  E. Haber,et al.  Mitogen-activated protein kinase phosphatase-1 in rat arterial smooth muscle cell proliferation. , 1996, The Journal of clinical investigation.

[83]  S. Grinstein,et al.  Insulin Activates a p21-activated Kinase in Muscle Cells via Phosphatidylinositol 3-Kinase* , 1996, The Journal of Biological Chemistry.

[84]  K. Irie,et al.  Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction , 1995, Science.

[85]  K. Chien,et al.  Ventricular Expression of a MLC-2v-ras Fusion Gene Induces Cardiac Hypertrophy and Selective Diastolic Dysfunction in Transgenic Mice (*) , 1995, The Journal of Biological Chemistry.

[86]  L. Zon,et al.  Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1 , 1994, Nature.

[87]  Michael J. Fry,et al.  Phosphatidylinositol-3-OH kinase direct target of Ras , 1994, Nature.

[88]  G. Dorn,et al.  Myosin heavy chain regulation and myocyte contractile depression after LV hypertrophy in aortic-banded mice. , 1994, The American journal of physiology.

[89]  J. Ross,et al.  ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice. , 1994, The American journal of physiology.

[90]  R. Hammer,et al.  Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. , 1993, The Journal of clinical investigation.

[91]  Nanxin Li,et al.  The function of GRB2 in linking the insulin receptor to Ras signaling pathways. , 1993, Science.

[92]  M. Wigler,et al.  Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. , 1993, Science.

[93]  Julian Downward,et al.  Epidermal growth factor regulates p21 ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor , 1993, Cell.

[94]  R. Weinberg,et al.  Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation , 1993, Nature.

[95]  Sheila M. Thomas,et al.  Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases , 1992, Nature.

[96]  N. Maeda,et al.  Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. , 1992, Science.

[97]  A. Ullrich,et al.  The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling , 1992, Cell.

[98]  H. Ueno,et al.  Inhibition of PDGF beta receptor signal transduction by coexpression of a truncated receptor , 1991, Science.

[99]  M. Pfeffer,et al.  Ventricular Remodeling After Myocardial Infarction: Experimental Observations and Clinical Implications , 1990, Circulation.

[100]  C. Proud,et al.  Methods for studying signal-dependent regulation of translation factor activity. , 2007, Methods in enzymology.

[101]  Jiahuai Han,et al.  Activation and signaling of the p38 MAP kinase pathway , 2005, Cell Research.

[102]  Jonathan A. Cooper,et al.  Phosphorylation of mammalian eIF4E by Mnk1 and Mnk2: tantalizing prospects for a role in translation. , 2001, Progress in molecular and subcellular biology.

[103]  R. Davis,et al.  Signal transduction by the c-Jun N-terminal kinase. , 1999, Biochemical Society symposium.

[104]  G. Lamas,et al.  Ventricular remodeling after myocardial infarction. , 1993, Advances in experimental medicine and biology.