title: Cardiac hypertrophy induced by mitogen-activated protein kinase kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells.
abstract: Activation of stress-activated protein kinases, including the p38 and the c-Jun NH2-terminal kinases (JNK), have been associated with the onset of cardiac hypertrophy and cell death in response to hemodynamic overload and ischemia/reperfusion injury. Upon infection of cultured neonatal rat cardiac myocytes with recombinant adenoviral vectors expressing a wild type and a constitutively active mutant of MKK7 (or JNKK2), JNK was specifically activated without affecting other mitogen-activated protein kinases, including extracellular signal-regulated protein kinases and p38. Specific activation of the JNK pathway in cardiac myocytes induced characteristic features of hypertrophy, including an increase in cell size, elevated expression of atrial natriuretic factor, and induction of sarcomere organization. In contrast, co-activation of both JNK (by MKK7) and p38 (by MKK3 or MKK6) in cardiomyocytes led to an induction of cytopathic responses and suppression of hypertrophic responses. These data provide the first direct evidence that activation of JNK alone is sufficient to induce characteristic features of cardiac hypertrophy, thereby supporting an active role for the JNK pathway in the development of cardiac hypertrophy. The cytopathic response, as a result of co-activation of both JNK and p38, may contribute to the loss of contractile function and viability of cardiomyocytes following hemodynamic overload and cardiac ischemia/reperfusion injury.
authors.affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: B
authors.initials: B
authors.lastname: Su
authors.forename: V P
authors.initials: VP
authors.lastname: Sah
authors.forename: J H
authors.initials: JH
authors.lastname: Brown
authors.forename: J
authors.initials: J
authors.lastname: Han
authors.forename: K R
authors.initials: KR
authors.lastname: Chien
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000503:physiopathology*; D048429:Cell Size / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006352:Heart Ventricles / Q000201:enzymology*; D006801:Humans; D007511:Ischemia / Q000503:physiopathology; D048031:JNK Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000235:genetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000503:physiopathology; D012518:Sarcomeres / Q000648:ultrastructure; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases