Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis.

The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure. To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle-specific Raf-1-knockout (Raf CKO) mice with Cre-loxP-mediated recombination. The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality. The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes. The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal-regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls. The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis. These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism.

[1]  Jun Du,et al.  Binding activity of H-Ras is necessary for in vivo inhibition of ASK1 activity , 2004, Cell Research.

[2]  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.

[3]  M. Hori,et al.  Cardiac‐specific overexpression of a high Ca2+ affinity mutant of SERCA2a attenuates in vivo pressure overload cardiac hypertrophy , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  MasatsuguHori,et al.  Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy , 2002 .

[5]  Jing Chen,et al.  Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK–ERK independent mechanism , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  E. Wagner,et al.  Embryonic lethality and fetal liver apoptosis in mice lacking the c‐raf‐1 gene , 2001, The EMBO journal.

[7]  C. Pritchard,et al.  MEK kinase activity is not necessary for Raf‐1 function , 2001, The EMBO journal.

[8]  T Takahashi,et al.  ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis , 2001, EMBO reports.

[9]  E. Wagner,et al.  Protective Role of Raf-1 in Salmonella-Induced Macrophage Apoptosis , 2001, The Journal of experimental medicine.

[10]  Xuan Sun,et al.  Akt Phosphorylates and Negatively Regulates Apoptosis Signal-Regulating Kinase 1 , 2001, Molecular and Cellular Biology.

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

[12]  H. Ichijo,et al.  Execution of Apoptosis Signal-regulating Kinase 1 (ASK1)-induced Apoptosis by the Mitochondria-dependent Caspase Activation* , 2000, The Journal of Biological Chemistry.

[13]  J. Pouysségur,et al.  The p42/p44 MAP kinase pathway prevents apoptosis induced by anchorage and serum removal. , 2000, Molecular biology of the cell.

[14]  L. Rubin,et al.  Role of Apoptosis Signal-Regulating Kinase in Regulation of the c-Jun N-Terminal Kinase Pathway and Apoptosis in Sympathetic Neurons , 2000, Molecular and Cellular Biology.

[15]  K. Moelling,et al.  Phosphorylation and regulation of Raf by Akt (protein kinase B). , 1999, Science.

[16]  P. Rakic,et al.  The Jnk1 and Jnk2 Protein Kinases Are Required for Regional Specific Apoptosis during Early Brain Development , 1999, Neuron.

[17]  D. Baltimore,et al.  Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. , 1998, Science.

[18]  A. Clerk,et al.  Stimulation of the p38 Mitogen-activated Protein Kinase Pathway in Neonatal Rat Ventricular Myocytes by the G Protein–coupled Receptor Agonists, Endothelin-1 and Phenylephrine: A Role in Cardiac Myocyte Hypertrophy? , 1998, The Journal of cell biology.

[19]  S. Izumo,et al.  Apoptosis: basic mechanisms and implications for cardiovascular disease. , 1998, Circulation research.

[20]  K. Chien,et al.  Ventricular muscle-restricted targeting of the RXRalpha gene reveals a non-cell-autonomous requirement in cardiac chamber morphogenesis. , 1998, Development.

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

[22]  Y. Zou,et al.  Oxidative stress activates extracellular signal-regulated kinases through Src and Ras in cultured cardiac myocytes of neonatal rats. , 1997, The Journal of clinical investigation.

[23]  J. Downey,et al.  Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. , 1997, Journal of molecular and cellular cardiology.

[24]  J. Miyazaki,et al.  A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. , 1997, Biochemical and biophysical research communications.

[25]  B. A. French,et al.  Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo. , 1997, The Journal of clinical investigation.

[26]  K. Chien,et al.  The MEKK-JNK Pathway Is Stimulated by α1-Adrenergic Receptor and Ras Activation and Is Associated with in Vitroand in Vivo Cardiac Hypertrophy* , 1997, The Journal of Biological Chemistry.

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

[28]  J. Ross,et al.  Transthoracic echocardiography in models of cardiac disease in the mouse. , 1996, Circulation.

[29]  P. Sugden,et al.  Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach downregulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. , 1996, Circulation research.

[30]  J. Brown,et al.  Dissociation of p44 and p42 Mitogen-activated Protein Kinase Activation from Receptor-induced Hypertrophy in Neonatal Rat Ventricular Myocytes (*) , 1996, The Journal of Biological Chemistry.

[31]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[32]  P. Sugden,et al.  The Mitogen-activated Protein Kinase Kinase MEK1 Stimulates a Pattern of Gene Expression Typical of the Hypertrophic Phenotype in Rat Ventricular Cardiomyocytes (*) , 1995, The Journal of Biological Chemistry.

[33]  J. Frost,et al.  Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy , 1994, The Journal of cell biology.

[34]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.