Published Online
on July 5, 2005

A more recent version of this article appeared on August 1, 2005

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Submitted on November 21, 2004
Revised on December 9, 2004

Role of Natriuretic Peptide Receptor Guanylyl Cyclase-A in Myocardial Infarction Evaluated Using Genetically Engineered Mice

Michio Nakanishi; Yoshihiko Saito; Ichiro Kishimoto^*; Masaki Harada; Koichiro Kuwahara; Nobuki Takahashi; Rika Kawakami; Yasuaki Nakagawa; Keiji Tanimoto; Shinji Yasuno; Satoru Usami; Yuhao Li; Yuichiro Adachi; Akiyoshi Fukamizu; David L. Garbers; and Kazuwa Nakao

From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (M.N., I.K., M.H., K.K., N.T., R.K., Y.N., K.T., S.Y., S.U., Y.L., Y.A., K.N.), Japan; the First Department of Internal Medicine, Nara Medical University, Japan (Y.S.); the Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Ibaraki, Japan (A.F.); and the Howard Hughes Medical Institute and Department of Pharmacology, University of Texas, Southwestern Medical Center at Dallas (D.L.G.).

^* To whom correspondence should be addressed. E-mail: kishimot{at}ri.ncvc.go.jp.

Abstract--Although plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated early after myocardial infarction (MI), the significance is not fully understood. We therefore investigated the function of natriuretic peptides after induction of MI in knockout (KO) mice lacking the natriuretic peptide receptor guanylyl cyclase-A, the receptor for ANP and BNP. KO and wild-type (WT) mice were subjected to left coronary artery ligation and then followed up for 4 weeks. Irrespective of genotype, almost all deaths occurred within 1 week after induction of MI. KO mice showed significantly higher mortality because of a higher incidence of acute heart failure, which was associated with diminished water and sodium excretion and with higher cardiac levels of mRNAs encoding ANP, BNP, transforming growth factor-1, and type I collagen. By 4 weeks after infarction, left ventricular remodeling, including myocardial hypertrophy and fibrosis, and impairment of left ventricular systolic function were significantly more severe in KO than WT mice. Notably, the enhanced myocardial fibrosis seen in KO mice was virtually absent in infarcted double-KO mice, lacking guanylyl cyclase-A and angiotensin II type 1a receptors, although there was no improvement in survival and no attenuation of cardiac hypertrophy. Thus, guanylyl cyclase-A activation by endogenous cardiac natriuretic peptides protects against acute heart failure and attenuates chronic cardiac remodeling after MI. These beneficial effects are mediated partly through inhibition of the renin-angiotensin system (RAS), although RAS-independent protective actions of guanylyl cyclase-A are also suggested.

Key words: receptors, angiotensin • coronary artery disease • hypertrophy • remodeling

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