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

Abstract

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 Ϫ/Ϫ 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 ASK1Ϫ/Ϫ mice, LV ASK1 activation by Ang II was not detectable in ASK1 Ϫ/Ϫ mice, and p38 and c-Jun N-terminal kinase (JNK) activation was lesser in ASK Ϫ/Ϫ mice than in wild-type mice. Elevation of blood pressure by continuous Ang II infusion was comparable between ASK1Ϫ/Ϫ and wild-type mice. However, Ang II-induced cardiac hypertrophy and remodeling, including cardiomyocyte hypertrophy, cardiac hypertrophy-related mRNA upregulation, cardiomyocyte apoptosis, interstitial fibrosis, coronary arterial remodeling, and collagen gene upregulation, was significantly attenuated in ASK1 Ϫ/Ϫ mice compared with wild-type mice. These results provided the first in vivo evidence that ASK1 is the critical signaling molecule for Ang II-induced cardiac hypertrophy and remodeling. Thus, ASK1 is proposed to be a potential therapeutic target for cardiac diseases.

Role of Apoptosis Signal-Regulating Kinase-1-c-Jun NH2-Terminal Kinase-p38 Signaling in Voltage-Gated K+Channel Remodeling of the Failing Heart: Regulation by Thioredoxin

“…Indeed, we and others have shown evidence of post-translational redox regulation of Kv4 channels (23,41). Our current data also suggest that a key redox-sensitive factor participating in I to remodeling during chronic MI is ASK1, a mitogen-activated protein kinase kinase that activates JNK and p38 (12,13,29). ASK1 is uniquely regulated by oxidative stress through direct binding with reduced Trx1, which inhibits kinase activity (12,25,29,38,45).…”

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

“…Increased pAKT was maintained in hearts of diabetic caPI3K-Tg mice, and AKT was previously shown to directly inhibit apoptosis signal-regulating kinase 1 (ASK1) in response to oxidative stress [43]. Further, AKT1 or deficiency of ASK1 protects the heart against cardiac pathology [44][45][46]. Thus, PI3K (p110α) is likely to mediate protection, in part, by activation of AKT.…”

Novel Mechanism and Role of Angiotensin II–Induced Vascular Endothelial Injury in Hypertensive Diastolic Heart Failure

“…13 Furthermore, we have also reported that ASK1 is implicated in AII-induced cardiac hypertrophy and fibrosis. 12 Thus, ASK1 seems to be an important signaling molecule responsible for cardiovascular diseases. However, the precise role of ASK1 in AII-induced vascular endothelial injury remains to be defined.…”

“…Accumulating in vitro evidence indicates that ASK1 participates in not only apoptosis but also various cellular responses, including cell differentiation and growth, or gene expression. Previously, we have shown that ASK1 is responsible for cardiac hypertrophy and fibrosis, 12 vascular intimal hyperplasia, 13 and ischemia-induced angiogenesis. 14 Furthermore, other investigators have also reported that ASK1 is implicated in cardiac myocyte death and remodeling induced by ischemia.…”