Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling.
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 comparable between ASK1-/- 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-/- 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.
Izumiya
Yasuhiro
Y
Department of Pharmacology, Osaka City University Graduate School of Medical Science, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
Kim
Shokei
S
Izumi
Yasukatsu
Y
Yoshida
Kaoru
K
Yoshiyama
Minoru
M
Matsuzawa
Atsushi
A
Ichijo
Hidenori
H
Iwao
Hiroshi
H
D000804:Angiotensin II; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D001835:Body Weight / Q000235:genetics; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006339:Heart Rate / Q000235:genetics; D015918:Infusion Pumps, Implantable; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
D044140:Receptor, Angiotensin, Type 1; D013481:Superoxides; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482859:Map3k5 protein, mouse