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(Circulation. 2002;106:1722.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Guanylyl Cyclase-A Inhibits Angiotensin II Type 1A Receptor-Mediated Cardiac Remodeling, an Endogenous Protective Mechanism in the Heart

Yuhao Li, MD, PhD; Ichiro Kishimoto, MD, PhD; Yoshihiko Saito, MD, PhD; Masaki Harada, MD, PhD; Koichiro Kuwahara, MD, PhD; Takehiko Izumi, MD; Nobuki Takahashi, MD; Rika Kawakami, MD; Keiji Tanimoto, MD; Yasuaki Nakagawa, MD; Michio Nakanishi, MD; Yuichiro Adachi, PhD; David L. Garbers, PhD; Akiyoshi Fukamizu, PhD; Kazuwa Nakao, MD, PhD

From the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan; the Howard Hughes Medical Institute and Department of Pharmacology, University of Texas, Southwestern Medical Center at Dallas (D.L.G.); and the Center for Tsukuba Advanced Research Alliance, Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki, Japan (A.F.).

Correspondence to Yoshihiko Saito, 840 Shijo-cho, Kashihara, Nara, 834-8521, Japan. E-mail yssaitu{at}naramed-u.ac.jp

Background— Guanylyl cyclase (GC)-A, a natriuretic peptide receptor, lowers blood pressure and inhibits the growth of cardiac myocytes and fibroblasts. Angiotensin II (Ang II) type 1A (AT_1A), an Ang II receptor, regulates cardiovascular homeostasis oppositely. Disruption of GC-A induces cardiac hypertrophy and fibrosis, suggesting that GC-A protects the heart from abnormal remodeling. We investigated whether GC-A interacts with AT_1A signaling in the heart by target deletion and pharmacological blockade or stimulation of AT_1A in mice.

Methods and Results— We generated double-knockout (KO) mice for GC-A and AT_1A by crossing GC-A-KO mice and AT_1A-KO mice and blocked AT₁ with a selective antagonist, CS-866. The cardiac hypertrophy and fibrosis of GC-A-KO mice were greatly improved by deletion or pharmacological blockade of AT_1A. Overexpression of mRNAs encoding atrial natriuretic peptide, brain natriuretic peptide, collagens I and III, transforming growth factors ß₁ and ß₃, were also strongly inhibited. Furthermore, stimulation of AT_1A by exogenous Ang II at a subpressor dose significantly exacerbated cardiac hypertrophy and dramatically augmented interstitial fibrosis in GC-A-KO mice but not in wild-type animals.

Conclusions— These results suggest that cardiac hypertrophy and fibrosis of GC-A-deficient mice are partially ascribed to an augmented cardiac AT_1A signaling and that GC-A inhibits AT_1A signaling-mediated excessive remodeling.

Key Words: natriuretic peptides • angiotensin • receptors • heart diseases • remodeling

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