Apoptosis signal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling.

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 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.

• Authors: Yasuhiro Izumiya, Shokei Kim, Yasukatsu Izumi, Kaoru Yoshida, Minoru Yoshiyama, Atsushi Matsuzawa, Hidenori Ichijo, Hiroshi Iwao
• Journal: Circulation research (Circ Res) Vol. 93 Issue 9 Pg. 874-83 (Oct 31 2003) ISSN: 1524-4571 [Electronic] United States
• PMID: 14551246 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptor, Angiotensin, Type 1
• Superoxides
• Angiotensin II
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 5
• MAP Kinase Kinase Kinases
• Map3k5 protein, mouse

Topics

• Angiotensin II
• Animals
• Apoptosis (drug effects, physiology)
• Blood Pressure (drug effects, genetics)
• Body Weight (genetics)
• Cardiomegaly (chemically induced, enzymology, genetics, pathology)
• Coronary Vessels (drug effects, pathology)
• Disease Models, Animal
• Disease Progression
• Fibrosis (chemically induced, pathology)
• Gene Expression (drug effects)
• Heart Rate (genetics)
• Infusion Pumps, Implantable
• MAP Kinase Kinase Kinase 5
• MAP Kinase Kinase Kinases (deficiency, genetics, metabolism)
• Mice
• Mice, Knockout
• Mitogen-Activated Protein Kinases (metabolism)
• Myocardium (metabolism, pathology)
• Receptor, Angiotensin, Type 1 (metabolism)
• Superoxides (metabolism)
• Ventricular Remodeling (drug effects, physiology)