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Updated: Jun 19, 2026
Transverse Aortic Constriction in Mice
Published on: April 21, 2010
ASK1 regulates cardiomyocyte death but not hypertrophy in transgenic mice
Qinghang Liu1, Michelle A Sargent, Allen J York
1Department of Pediatrics, Division of Molecular Cardiovascular Biology, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA.
Rationale:
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.
Methods And 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.
Insights
Apoptosis signal-regulating kinase 1 (ASK1) does not directly cause cardiac hypertrophy. However, ASK1 overexpression increases cell death and cardiomyopathy susceptibility via a calcineurin-dependent pathway.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cell Signaling
Background:
- Apoptosis signal-regulating kinase 1 (ASK1) is a key kinase in stress-induced cell death pathways.
- ASK1's role in cardiac hypertrophy in vivo is not well understood and remains controversial.
Purpose of the Study:
- To investigate the role of ASK1 in cardiac hypertrophy and pathology using a gain-of-function mouse model.
- To elucidate the downstream signaling pathways and mechanisms involved in ASK1-mediated cardiac effects.
Main Methods:
- Generated cardiac-specific, inducible ASK1-overexpressing transgenic mice.
- Assessed cardiac hypertrophy and pathology after pressure-overload stimulation and myocardial infarction.
- Analyzed downstream signaling pathways including MAPK, calcineurin-NFAT, and apoptosis markers.
Main Results:
- ASK1 overexpression did not induce cardiac hypertrophy or pathology in basal conditions or upon hypertrophic stimuli.
- ASK1 overexpression significantly increased cardiomyopathy, cell death (TUNEL), and ischemia-reperfusion injury.
- Downstream signaling revealed activation of MKK4/6-JNK, inhibition of calcineurin-NFAT, and increased Bax induction.
Conclusions:
- ASK1 does not directly regulate cardiac hypertrophy in vivo.
- ASK1 promotes cardiomyopathy and cell death, partly through a calcineurin-dependent mechanism.
