ASK1 regulates cardiomyocyte death but not hypertrophy in transgenic mice.
BACKGROUND
Apoptosis signal-regulating kinase (ASK)1 is a central upstream kinase in the greater mitogen-activated protein kinase cascade that mediates growth and death decisions in cardiac myocytes in response to diverse pathological stimuli.


OBJECTIVE
However, the role that ASK1 plays in regulating the cardiac hypertrophic response in vivo remains controversial.


RESULTS
Here, we generated mice with cardiac-specific and inducible overexpression of ASK1 in the heart to assess its gain-of-function effect. ASK1 transgenic mice exhibited no induction of cardiac hypertrophy or pathology at 3 and 12 months of age, and these mice showed an identical hypertrophic response to controls following 2 weeks of pressure-overload stimulation or isoproterenol infusion. Although ASK1 overexpression did not alter the cardiac hypertrophic response, it promoted cardiomyopathy and greater TUNEL following pressure-overload stimulation and myocardial infarction. Indeed, ASK1 transgenic mice showed a greater than 2-fold increase in ischemia reperfusion-induced injury to the heart compared with controls. Examination of downstream signaling showed a prominent activation of mitogen-activated protein kinase kinase 4/6 and c-Jun NH(2)-terminal kinase (JNK)1/2 (but not p38 or extracellular signal-regulated kinases [ERKs]), inhibition of calcineurin-NFAT (nuclear factor of activated T cells), and induction of Bax in the hearts of ASK1 transgenic mice following 1 and 8 weeks of pressure-overload stimulation. Mechanistically, cardiomyopathy associated with ASK1 overexpression after 8 weeks of pressure overload was significantly reduced in the calcineurin Abeta-null (CnAbeta(-/-)) background.


CONCLUSIONS
These results indicate that ASK1 does not directly regulate the cardiac hypertrophic response in vivo, but it does alter cell death and propensity to cardiomyopathy, in part, through a calcineurin-dependent mechanism.
Liu
Qinghang
Q
Department of Pediatrics, Division of Molecular Cardiovascular Biology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Sargent
Michelle A
MA
York
Allen J
AJ
Molkentin
Jeffery D
JD
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D019703:Calcineurin; D002118:Calcium