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(Circulation. 2005;111:3095-3104.)
© 2005 American Heart Association, Inc.

Heart Failure

Calcineurin–Nuclear Factor of Activated T Cells Pathway–Dependent Cardiac Remodeling in Mice Deficient in Guanylyl Cyclase A, a Receptor for Atrial and Brain Natriuretic Peptides

Takeshi Tokudome, MD, PhD; Takeshi Horio, MD, PhD; Ichiro Kishimoto, MD, PhD; Takeshi Soeki, MD, PhD; Kenji Mori, PhD; Yuhei Kawano, MD, PhD; Masakazu Kohno, MD, PhD; David L. Garbers, PhD; Kazuwa Nakao, MD, PhD; Kenji Kangawa, PhD

From the Department of Biochemistry, Research Institute (T.T., I.K., T.S., K.M., K.K.) and Department of Medicine (T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; the Second Department of Internal Medicine (M.K.), Kagawa University Faculty of Medicine, Kagawa, Japan; the Howard Hughes Medical Institute and Department of Pharmacology (D.L.G), University of Texas Southwestern Medical Center at Dallas; and the Department of Medicine and Clinical Science (K.N), Kyoto University Graduate School of Medicine, Kyoto, Japan.

Correspondence to Ichiro Kishimoto, MD, Department of Biochemistry, National Cardiovascular Center Research Institute, 5-7-1, Fujishirodai, Suita, Osaka 565-8565, Japan. E-mail kishimot{at}ri.ncvc.go.jp

Received October 3, 2004; revision received January 23, 2005; accepted February 3, 2005.

Background— Although disruption of guanylyl cyclase (GC) A, a natriuretic peptide receptor, induces cardiac hypertrophy and fibrosis, the molecular mechanism underlying these effects are not well understood. In this study, we examined the role of calcineurin, a calcium-dependent phosphatase, in cardiac remodeling in GCA-knockout (GCA-KO) mice.

Methods and Results— At 14 weeks of age, calcineurin activity, nuclear translocation of nuclear factor of activated T cells c3 (NFATc3), and modulatory calcineurin-interacting protein 1 (MCIP1) gene expressions were increased in the hearts of GCA-KO mice compared with wild-type (WT) mice. Blockade of calcineurin activation by FK506 (6 mg/kg body weight administered subcutaneously once a day from 10 to 14 weeks of age) significantly decreased the heart-to-body weight ratio, cardiomyocyte size, and collagen volume fraction in GCA-KO mice, whereas FK506 did not affect these parameters in WT mice. Overexpression of atrial and brain natriuretic peptides, collagen, and fibronectin mRNAs in GCA-KO mice was also attenuated by FK506. Electrophoretic mobility shift assays demonstrated that GATA4 DNA-binding activity was increased in GCA-KO mice, and this increase was inhibited by calcineurin blockade. In neonatal cultured cardiac myocytes, inhibition of GCA by HS142-1 (100 µg/mL) increased basal and phenylephrine (10^–6 mol/L)-stimulated calcineurin activity, nuclear translocation of NFATc3, and MCIP1 mRNA expression. In contrast, activation of GCA by atrial natriuretic peptide (10^–6 mol/L) inhibited phenylephrine (10^–6 mol/L)-stimulated nuclear translocation of NFATc3.

Conclusions— These results suggest that activation of cardiac GCA by locally secreted natriuretic peptides protects the heart from excessive cardiac remodeling by inhibiting the calcineurin-NFAT pathway.

Key Words: calcineurin • fibrosis • hypertrophy • natriuretic peptides • remodeling

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