This Article Full Text Full Text (PDF) All Versions of this Article: 111/23/3095    most recent CIRCULATIONAHA.104.510594v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tokudome, T. Articles by Kangawa, K. Search for Related Content PubMed PubMed Citation Articles by Tokudome, T. Articles by Kangawa, K. Related Collections Remodeling Hypertrophy

(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

This article has been cited by other articles:

				T. Tokudome, I. Kishimoto, K. Yamahara, T. Osaki, N. Minamino, T. Horio, K. Sawai, Y. Kawano, M. Miyazato, M. Sata, et al. Impaired Recovery of Blood Flow After Hind-Limb Ischemia in Mice Lacking Guanylyl Cyclase-A, a Receptor for Atrial and Brain Natriuretic Peptides Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1516 - 1521. [Abstract] [Full Text] [PDF]

				S. Hsu, T. Nagayama, N. Koitabashi, M. Zhang, L. Zhou, D. Bedja, K. L. Gabrielson, J. D. Molkentin, D. A. Kass, and E. Takimoto Phosphodiesterase 5 inhibition blocks pressure overload-induced cardiac hypertrophy independent of the calcineurin pathway Cardiovasc Res, February 1, 2009; 81(2): 301 - 309. [Abstract] [Full Text] [PDF]

				T. Tokudome, I. Kishimoto, T. Horio, Y. Arai, D. O. Schwenke, J. Hino, I. Okano, Y. Kawano, M. Kohno, M. Miyazato, et al. Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart Circulation, May 6, 2008; 117(18): 2329 - 2339. [Abstract] [Full Text] [PDF]

				D. O. Schwenke, T. Tokudome, M. Shirai, H. Hosoda, T. Horio, I. Kishimoto, and K. Kangawa Exogenous Ghrelin Attenuates the Progression of Chronic Hypoxia-Induced Pulmonary Hypertension in Conscious Rats Endocrinology, January 1, 2008; 149(1): 237 - 244. [Abstract] [Full Text] [PDF]

				D. A. Kass, H. C. Champion, and J. A. Beavo Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation Circ. Res., November 26, 2007; 101(11): 1084 - 1095. [Abstract] [Full Text] [PDF]

				D. A. Kass, E. Takimoto, T. Nagayama, and H. C. Champion Phosphodiesterase regulation of nitric oxide signaling Cardiovasc Res, July 15, 2007; 75(2): 303 - 314. [Abstract] [Full Text] [PDF]

				E. Takimoto and D. A. Kass Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling Hypertension, February 1, 2007; 49(2): 241 - 248. [Full Text] [PDF]

				T. Nishikimi, N. Maeda, and H. Matsuoka The role of natriuretic peptides in cardioprotection Cardiovasc Res, February 1, 2006; 69(2): 318 - 328. [Abstract] [Full Text] [PDF]