Activation of nuclear factor- B is necessary for myotrophin-induced cardiac hypertrophy

he transcription factor nuclear factorB (NFB) regulates expression of a variety of genes involved in immune responses, inflammation, proliferation, and programmed cell death (apoptosis). Here, we show that in rat neonatal ventricular cardiomyocytes, activation of NFB is involved in the hypertrophic response induced by myotrophin, a hypertrophic activator identified from spontaneously hypertensive rat heart and cardiomyopathic human hearts. Myotrophin treatment stimulated NFB nuclear translocation and transcriptional activity, accompanied by I Bphosphorylation and degradation. Consistently, myotrophin-induced NFB activation was enhanced by T wild-type I B kinase (IKK) and abolished by the dominantnegative IKK or a general PKC inhibitor, calphostin C. Importantly, myotrophin-induced expression of two hypertrophic genes (atrial natriuretic factor [ANF] and c-myc ) and also enhanced protein synthesis were partially inhibited by a potent NFB inhibitor, pyrrolidine dithio-carbamate (PDTC), and calphostin C. Expression of the dominantnegative form of I Bor IKK also partially inhibited the transcriptional activity of ANF induced by myotrophin. These findings suggest that the PKC–IKK–NFB pathway may play a critical role in mediating the myotrophin-induced hypertrophic response in cardiomyocytes.

[1]  N. Sivasubramanian,et al.  Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFκB p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers* , 2002, The Journal of Biological Chemistry.

[2]  Sudhiranjan Gupta,et al.  Myotrophin–κB DNA interaction in the initiation process of cardiac hypertrophy , 2002 .

[3]  A. Lin,et al.  Activation of NF-κB is required for hypertrophic growth of primary rat neonatal ventricular cardiomyocytes , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  N. Paran,et al.  Activation of NF-κB by hepatitis B virus X protein through an IκB kinase-independent mechanism , 2001 .

[5]  David L. Williams,et al.  Early activation of IKKβ during in vivo myocardial ischemia , 2001 .

[6]  R. Hofer-Warbinek,et al.  The Transcription Factor NF-κB and the Regulation of Vascular Cell Function , 2000 .

[7]  W. V. Berghe,et al.  Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. , 2000, Biochemical pharmacology.

[8]  D. Thuerauf,et al.  p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system. , 2000, The Journal of biological chemistry.

[9]  D. Thuerauf,et al.  p38 MAPK and NF-κB Collaborate to Induce Interleukin-6 Gene Expression and Release , 2000, The Journal of Biological Chemistry.

[10]  J. Frost,et al.  Stimulation of NFκB Activity by Multiple Signaling Pathways Requires PAK1* , 2000, The Journal of Biological Chemistry.

[11]  K. Chien.  Meeting Koch's postulates for calcium signaling in cardiac hypertrophy. , 2000, The Journal of clinical investigation.

[12]  A. Israël.  The IKK complex: an integrator of all signals that activate NF-κB? , 2000 .

[13]  K. Knudtson,et al.  The p38 Mitogen-activated Protein Kinase Is Required for NF-κB-dependent Gene Expression , 1999, The Journal of Biological Chemistry.

[14]  Michael Karin,et al.  The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[15]  K. Chien,et al.  Stress Pathways and Heart Failure , 1999, Cell.

[16]  E. Zandi,et al.  Bridging the Gap: Composition, Regulation, and Physiological Function of the IκB Kinase Complex , 1999, Molecular and Cellular Biology.

[17]  E. Olson,et al.  Prevention of cardiac hypertrophy by calcineurin inhibition: hope or hype? , 1999, Circulation research.

[18]  M. Mcqueney,et al.  cDNA sequence and characterization of the gene that encodes human myotrophin/V-1 protein, a mediator of cardiac hypertrophy. , 1999, Journal of molecular and cellular cardiology.

[19]  R. Kao,et al.  Early activation of transcription factor NF-κB during ischemia in perfused rat heart. , 1999, American journal of physiology. Heart and circulatory physiology.

[20]  A. Lin,et al.  Coordinate Regulation of IκB Kinases by Mitogen-Activated Protein Kinase Kinase Kinase 1 and NF-κB-Inducing Kinase , 1998, Molecular and Cellular Biology.

[21]  M. E. Ritchie.  Nuclear Factor-κB Is Selectively and Markedly Activated in Humans With Unstable Angina Pectoris , 1998 .

[22]  J. Bonner,et al.  Role of Nuclear Factor-κB and Mitogen-Activated Protein Kinase Signaling Pathways in IL-1β-Mediated Induction of α-PDGF Receptor Expression in Rat Pulmonary Myofibroblasts , 1998, The Journal of Immunology.

[23]  E. Zandi,et al.  IKK-γ is an essential regulatory subunit of the IκB kinase complex , 1998, Nature.

[24]  Mark A Sussman,et al.  Prevention of cardiac hypertrophy in mice by calcineurin inhibition. , 1998, Science.

[25]  A. Clerk,et al.  Cellular mechanisms of cardiac hypertrophy , 1998, Journal of Molecular Medicine.

[26]  Ebrahim Zandi,et al.  Direct Phosphorylation of IκB by IKKα and IKKβ: Discrimination Between Free and NF-κB-Bound Substrate , 1998 .

[27]  G. Courtois,et al.  Complementation Cloning of NEMO, a Component of the IκB Kinase Complex Essential for NF-κB Activation , 1998, Cell.

[28]  B. Price,et al.  An essential role of NFκB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia , 1998, FEBS letters.

[29]  P. Sil,et al.  Increased protein kinase C activity in myotrophin-induced myocyte growth. , 1998, Circulation research.

[30]  A. Lin,et al.  Opposing Effects of Jun Kinase and p38 Mitogen-Activated Protein Kinases on Cardiomyocyte Hypertrophy , 1998, Molecular and Cellular Biology.

[31]  Jeffrey Robbins,et al.  A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy , 1998, Cell.

[32]  S. Ghosh,et al.  Signal transduction through NF-κB , 1998 .

[33]  R. A. Hunt,et al.  Molecular mechanisms of angiotensin II in modulating cardiac function: intracardiac effects and signal transduction pathways. , 1997, Journal of molecular and cellular cardiology.

[34]  M. Garami,et al.  Mechanical Strain Increases Expression of the Brain Natriuretic Peptide Gene in Rat Cardiac Myocytes* , 1997, The Journal of Biological Chemistry.

[35]  Mike Rothe,et al.  IκB Kinase-β: NF-κB Activation and Complex Formation with IκB Kinase-α and NIK , 1997 .

[36]  E. Zandi,et al.  The IκB Kinase Complex (IKK) Contains Two Kinase Subunits, IKKα and IKKβ, Necessary for IκB Phosphorylation and NF-κB Activation , 1997, Cell.

[37]  David M. Rothwarf,et al.  A cytokine-responsive IκB kinase that activates the transcription factor NF-κB , 1997, Nature.

[38]  D. Goeddel,et al.  Identification and Characterization of an IκB Kinase , 1997, Cell.

[39]  S. Ghosh,et al.  Rel/NF-?B and I?B proteins: an overview , 1997 .

[40]  David Baltimore,et al.  NF-κB: Ten Years After , 1996, Cell.

[41]  Y. Mori,et al.  Mechanical stretch induces enhanced expression of angiotensin II receptor subtypes in neonatal rat cardiac myocytes. , 1996, Circulation research.

[42]  C. Mueller-Dieckmann,et al.  Tyrosine Phosphorylation of IκB-α Activates NF-κB without Proteolytic Degradation of IκB-α , 1996, Cell.

[43]  K. Catt,et al.  Angiotensin receptors and their antagonists. , 1996, The New England journal of medicine.

[44]  T. Maniatis,et al.  Site-Specific Phosphorylation of IκBα by a Novel Ubiquitination-Dependent Protein Kinase Activity , 1996, Cell.

[45]  N. Sivasubramanian,et al.  Cardiac Myotrophin Exhibits rel/NF-κB Interacting Activity in Vitro(*) , 1996, The Journal of Biological Chemistry.

[46]  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.

[47]  A. Baldwin,et al.  Mechanistic aspects of NF-κB regulation: The emerging role of phosphorylation and proteolysis , 1995 .

[48]  T. Maniatis,et al.  Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway. , 1995, Genes & development.

[49]  P. Sil,et al.  Quantification of myotrophin from spontaneously hypertensive and normal rat hearts. , 1995, Circulation research.

[50]  T. Maniatis,et al.  NF-κB: A lesson in family values , 1995, Cell.

[51]  A. Thorburn,et al.  Raf-1 kinase activity is necessary and sufficient for gene expression changes but not sufficient for cellular morphology changes associated with cardiac myocyte hypertrophy. , 1994, The Journal of biological chemistry.

[52]  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.

[53]  Junichi Sadoshima,et al.  Molecular characterization of angiotensin II--induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. Critical role of the AT1 receptor subtype. , 1993, Circulation research.

[54]  K. Misono,et al.  Myotrophin in human cardiomyopathic heart. , 1993, Circulation research.

[55]  C. McTiernan,et al.  Myotrophin induces early response genes and enhances cardiac gene expression. , 1993, Hypertension.

[56]  D. Belin,et al.  Transient translational silencing by reversible mRNA deadenylation , 1992, Cell.

[57]  J. Sadoshima,et al.  Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. , 1992, The Journal of biological chemistry.

[58]  H. Schunkert,et al.  Age-related differences in the expression of proto-oncogene and contractile protein genes in response to pressure overload in the rat myocardium. , 1992, The Journal of clinical investigation.

[59]  S. Chien,et al.  Regulation of cardiac gene expression during myocardial growth and hypertrophy: molecular studies of an adaptive physiologic response , 1991, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[60]  J. Franklyn,et al.  Role of proto-oncogenes in the control of myocardial cell growth and function. , 1991, Clinical science.

[61]  K. Baker,et al.  Cardiac Hypertrophy: Mechanical, Neural, and Endocrine Dependence , 1991 .

[62]  D E Manyari,et al.  Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. , 1990, The New England journal of medicine.

[63]  B. Healy,et al.  Myotrophin: purification of a novel peptide from spontaneously hypertensive rat heart that influences myocardial growth. , 1990, The Journal of biological chemistry.

[64]  V. Sukhatme,et al.  Alpha- and beta-adrenergic stimulation induces distinct patterns of immediate early gene expression in neonatal rat myocardial cells. fos/jun expression is associated with sarcomere assembly; Egr-1 induction is primarily an alpha 1-mediated response. , 1990, The Journal of biological chemistry.

[65]  J. Michel,et al.  Atrial natriuretic factor gene expression in rat ventricle during experimental hypertension. , 1989, The American journal of physiology.

[66]  R. Matsuoka,et al.  Myosin heavy chain messenger RNA and protein isoform transitions during cardiac hypertrophy. Interaction between hemodynamic and thyroid hormone-induced signals. , 1987, The Journal of clinical investigation.

[67]  S. Coughlin,et al.  Cardiac myocyte hypertrophy is associated with c-myc protooncogene expression. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[68]  J. Michel,et al.  Myocardial recruitment during ANF mRNA increase with volume overload in the rat. , 1986, The American journal of physiology.

[69]  David Baltimore,et al.  Multiple nuclear factors interact with the immunoglobulin enhancer sequences , 1986, Cell.

[70]  M. Runge,et al.  Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-κB (NF-κB) transcription factor , 2004, Molecular and Cellular Biochemistry.

[71]  M. Runge,et al.  Angiotensin II induces gene transcription through cell-type-dependent effects on the nuclear factor-kappaB (NF-kappaB) transcription factor. , 2000, Molecular and cellular biochemistry.

[72]  Xianglin Shi,et al.  New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. , 1999, Clinical chemistry.

[73]  M. Monick,et al.  The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). , 1999, The Journal of biological chemistry.

[74]  A. Baldwin,et al.  THE NF-κB AND IκB PROTEINS: New Discoveries and Insights , 1996 .

[75]  T. McKinsey,et al.  Coupling of a Signal Response Domain in IkBato Multiple Pathways for NF-kB Activation , 1995 .

[76]  I. Moraru,et al.  Gene expression in acute myocardial stress. Induction by hypoxia, ischemia, reperfusion, hyperthermia and oxidative stress. , 1995, Journal of molecular and cellular cardiology.

[77]  B. Nadal-Ginard,et al.  Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[78]  R. Roeder,et al.  Eukaryotic gene transcription with purified components. , 1983, Methods in enzymology.

[79]  Nuclear Factor- (cid:107) B Plays an Essential Role in the Late Phase of Ischemic Preconditioning in Conscious Rabbits , 2022 .