Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes
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- Beate Fiedler
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Suzanne M. Lohmann
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Albert Smolenski
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Stephan Linnemüller
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Burkert Pieske
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Frank Schröder
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Jeffery D. Molkentin
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Helmut Drexler
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
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- Kai C. Wollert
- Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany; Institute for Clinical Biochemistry and Pathobiochemistry, University of Würzburg, 97080 Würzburg, Germany; Department of Cardiology and Pneumology, University of Göttingen, 37075 Göttingen, Germany; and Department of Molecular Cardiovascular Biology, Children's Hospital Medical Center, Cincinnati, OH 45229-3039
書誌事項
- 公開日
- 2002-08-12
- DOI
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- 10.1073/pnas.162100799
- 公開者
- Proceedings of the National Academy of Sciences
この論文をさがす
説明
<jats:p> Recent investigation has focused on identifying signaling pathways that inhibit cardiac hypertrophy, a major risk factor for cardiovascular morbidity and mortality. In this context, nitric oxide (NO), signaling via cGMP and cGMP-dependent protein kinase type I (PKG I), has been recognized as a negative regulator of cardiac myocyte (CM) hypertrophy. However, the underlying mechanisms are poorly understood. Here, we show that PKG I inhibits CM hypertrophy by targeting the calcineurin-NFAT signaling pathway. Calcineurin, a Ca <jats:sup>2+</jats:sup> -dependent phosphatase, promotes hypertrophy in part by activating NFAT transcription factors which induce expression of hypertrophic genes, including brain natriuretic peptide (BNP). Activation of PKG I by NO/cGMP in CM suppressed NFAT transcriptional activity, BNP induction, and cell enlargement in response to α <jats:sub>1</jats:sub> -adrenoreceptor stimulation but not in response to adenoviral expression of a Ca <jats:sup>2+</jats:sup> -independent, constitutively active calcineurin mutant, thus demonstrating NO-cGMP-PKG I inhibition of calcineurin-NFAT signaling upstream of calcineurin. PKG I suppressed single L-type Ca <jats:sup>2+</jats:sup> -channel open probability, [Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> transient amplitude, and, most importantly, L-type Ca <jats:sup>2+</jats:sup> -channel current-induced NFAT activation, indicating that PKG I targets Ca <jats:sup>2+</jats:sup> -dependent steps upstream of calcineurin. Adenoviral expression of PKG I enhanced NO/cGMP inhibitory effects upstream of calcineurin, confirming that PKG I mediates NO/cGMP inhibition of calcineurin-NFAT signaling. In CM overexpressing PKG I, NO/cGMP also suppressed BNP induction and cell enlargement but not NFAT activation elicited by constitutively active calcineurin, which is consistent with additional, NFAT-independent inhibitory effect(s) of PKG I downstream of calcineurin. Inhibition of calcineurin-NFAT signaling by PKG I provides a framework for understanding how NO inhibits cardiac myocyte hypertrophy. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 99 (17), 11363-11368, 2002-08-12
Proceedings of the National Academy of Sciences
