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Fiedler, B; Lohmann, SM; Smolenski, A; Linnemuller, S; Pieske, B; Schroder, F; Molkentin, JD; Drexler, H; Wollert, KC.
Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes.
Proc Natl Acad Sci U S A. 2002; 99(17):11363-11368 Doi: 10.1073/pnas.162100799 [OPEN ACCESS]
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Co-authors Med Uni Graz: Pieske Burkert Mathias
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Abstract:: 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 Ca2+-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 alpha(1)-adrenoreceptor stimulation but not in response to adenoviral expression of a Ca2+-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 Ca2+-channel open probability, [Ca2+]i transient amplitude, and, most importantly, L-type Ca2+-channel current-induced NFAT activation, indicating that PKG I targets Ca2+-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.
Find related publications in this database (using NLM MeSH Indexing): Animals -; Animals, Newborn -; Calcineurin - antagonists and inhibitors; Calcium Channels, L-Type - physiology; Calcium Signaling - physiology; Cardiomegaly - enzymology; Cells, Cultured - enzymology; Cyclic GMP - analogs and derivatives; Cyclic GMP-Dependent Protein Kinases - antagonists and inhibitors; DNA-Binding Proteins - antagonists and inhibitors; Enzyme Activation - antagonists and inhibitors; Heart - physiology; Heart Ventricles - physiology; Ion Channel Gating - physiology; Luciferases - genetics; Myocardium - metabolism; NFATC Transcription Factors - metabolism; Natriuretic Peptide, Brain - genetics; Nuclear Proteins - genetics; Plasmids - genetics; Probability - genetics; Promoter Regions (Genetics) - genetics; Rats - genetics; Rats, Sprague-Dawley - genetics; Signal Transduction - physiology; Thionucleotides - pharmacology; Transcription Factors - antagonists and inhibitors; Transcription, Genetic - antagonists and inhibitors; Transfection - antagonists and inhibitors