Apoptosis Signal-Regulating Kinase 1 Plays a Pivotal Role in Angiotensin II–Induced Cardiac Hypertrophy and Remodeling

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Abstract
Multiple lines of evidence establish that angiotensin II (Ang II) induces not only hypertension but also directly contributes to cardiac diseases. Apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, plays a key role in stress-induced cellular responses. However, nothing is known about the role of ASK1 in cardiac hypertrophy and remodeling in vivo. In this study, by using mice deficient in ASK1 (ASK1−/− mice), we investigated the role of ASK1 in cardiac hypertrophy and remodeling induced by Ang II. Left ventricular (LV) ASK1 was activated by Ang II infusion in wild-type mice, which was mediated by angiotensin II type 1 receptor and superoxide. Although Ang II-induced hypertensive effect was comparable to wild-type and ASK1−/− mice, LV ASK1 activation by Ang II was not detectable in ASK1−/− mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesser in ASK−/− mice than in wild-type mice. Elevation of blood pressure by continuous Ang II infusion was ...