{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T19:53:21Z","timestamp":1770753201456,"version":"3.50.0"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2009,11,20]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:underline>Rationale<\/jats:underline>\n                :\n              <\/jats:italic>\n            <\/jats:bold>\n            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.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:underline>Objective<\/jats:underline>\n                :\n              <\/jats:italic>\n            <\/jats:bold>\n            However, the role that ASK1 plays in regulating the cardiac hypertrophic response in vivo remains controversial.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:underline>Methods and Results<\/jats:underline>\n                :\n              <\/jats:italic>\n            <\/jats:bold>\n            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\n            <jats:sub>2<\/jats:sub>\n            -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 A\u03b2\u2013null (\n            <jats:italic>CnA<\/jats:italic>\n            \u03b2\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            ) background.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>\n                <jats:underline>Conclusions<\/jats:underline>\n                :\n              <\/jats:italic>\n            <\/jats:bold>\n            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.\n          <\/jats:p>","DOI":"10.1161\/circresaha.109.200741","type":"journal-article","created":{"date-parts":[[2009,10,9]],"date-time":"2009-10-09T02:15:49Z","timestamp":1255054549000},"page":"1110-1117","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":75,"title":["ASK1 Regulates Cardiomyocyte Death but Not Hypertrophy in Transgenic Mice"],"prefix":"10.1161","volume":"105","author":[{"given":"Qinghang","family":"Liu","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics, Division of Molecular Cardiovascular Biology (Q.L., M.A.S., A.J.Y., J.D.M.), and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children\u2019s Hospital Medical Center, Ohio."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle A.","family":"Sargent","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Division of Molecular Cardiovascular Biology (Q.L., M.A.S., A.J.Y., J.D.M.), and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children\u2019s Hospital Medical Center, Ohio."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen J.","family":"York","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Division of Molecular Cardiovascular Biology (Q.L., M.A.S., A.J.Y., J.D.M.), and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children\u2019s Hospital Medical Center, Ohio."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffery D.","family":"Molkentin","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics, Division of Molecular Cardiovascular Biology (Q.L., M.A.S., A.J.Y., J.D.M.), and the Howard Hughes Medical Institute (J.D.M.), University of Cincinnati, Cincinnati Children\u2019s Hospital Medical Center, 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