Genetic Disruption of Angiotensin II Type 1a Receptor Improves Long-Term Survival of Mice With Chronic Severe Aortic Regurgitation

Michio Nakanishi; Masaki Harada; Ichiro Kishimoto; Koichiro Kuwahara; Rika Kawakami; Yasuaki Nakagawa; Shinji Yasuno; Satoru Usami; Hideyuki Kinoshita; Yuichiro Adachi; Akiyoshi Fukamizu; Yoshihiko Saito; Kazuwa Nakao

doi:10.1253/circj.71.1310

Experimental Investigation

Genetic Disruption of Angiotensin II Type 1a Receptor Improves Long-Term Survival of Mice With Chronic Severe Aortic Regurgitation

Michio Nakanishi, Masaki Harada, Ichiro Kishimoto, Koichiro Kuwahara, Rika Kawakami, Yasuaki Nakagawa, Shinji Yasuno, Satoru Usami, Hideyuki Kinoshita, Yuichiro Adachi, Akiyoshi Fukamizu, Yoshihiko Saito, Kazuwa Nakao

Author information

Michio Nakanishi
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Masaki Harada
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Ichiro Kishimoto
Department of Biochemistry, National Cardiovascular Center, Research Institute
Koichiro Kuwahara
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Rika Kawakami
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Yasuaki Nakagawa
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Shinji Yasuno
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Satoru Usami
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Hideyuki Kinoshita
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Yuichiro Adachi
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
Akiyoshi Fukamizu
Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba
Yoshihiko Saito
First Department of Internal Medicine, Nara Medical University
Kazuwa Nakao
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine

Keywords: Angiotensin, Fibrosis, Heart failure, Hypertrophy, Valvular disease

JOURNAL FREE ACCESS

2007 Volume 71 Issue 8 Pages 1310-1316

DOI https://doi.org/10.1253/circj.71.1310

Details

Abstract

Background Aortic regurgitation (AR) causes left ventricular (LV) volume overload, leading to progressive LV dilatation and dysfunction. In the present study it was examined whether blockade of angiotensin II type 1 receptor (AT1) could improve survival in cases of chronic severe AR. Methods and Results AR was induced by puncturing the aortic valves of wild-type (WT) and AT1a knockout (KO) mice. Mice that survived for 4 weeks after the operation were deemed to be a model of chronic severe AR and were followed up for 50 weeks (WT, n=29; KO, n=31). Baseline measurements made 4 weeks after surgery showed similar LV cavity and function in both genotypes. These conditions progressively worsened in both genotypes, but 16 weeks after baseline, KO mice showed significantly less LV dilatation, hypertrophy and interstitial fibrosis than WT mice. Cardiac mRNA expression of B-type natriuretic peptide and type I collagen was lower in KO than WT mice. The 50-week mortality rate was significantly lower among KO (45.2%) than WT (86.2%) mice, and postmortem findings indicated that the lower mortality was attributable to a lower incidence of congestive heart failure. Conclusions In cases of chronic severe AR, blockade of AT1 attenuates the progression of LV dilatation, hypertrophy and fibrosis, thereby mitigating heart failure and improving long-term survival. (Circ J 2007; 71: 1310 - 1316)

Corresponding author

Register with J-STAGE for free!