ArticleProceedings of the National Academy of Sciences of the United States of America2002
Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytes.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers, 1 of them a synthesis that pooled it.
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Who cites it
101 citing papers in PubMed, 1 synthesis or guideline pooled it, 277 citations in OpenAlex.
- Cardiovascular Effects of Stimulators of Soluble Guanylate Cyclase Administration: A Meta-analysis of Randomized Controlled Trials.Current atherosclerosis reports · 2024Pooled it
- Calcineurin/NFAT signaling in the temporal integration of Ca²⁺ stress in neurodegeneration.Cell death discovery · 2026Review
- Hederagenin Attenuates Cardiac Remodeling by Targeting Phosphodiesterase 9A.Phytotherapy research : PTR · 2026Article
- Vericiguat: A New Horizon for Heart Failure Treatment.Reviews in cardiovascular medicine · 2026Review
- Review
- Soluble guanylate cyclase modulation in heart failure and chronic kidney disease: mechanisms, clinical evidence, and translational boundaries.Frontiers in pharmacology · 2026Review
- NAMPT modulates muscle fiber type transition in PAD myopathy via the cGMP-PKG signaling pathway.Biology direct · 2025Article
- Targeting the NO-sGC-cGMP Pathway: Mechanisms of Action of Vericiguat in Chronic Heart Failure.Cells · 2025Review
- Influence of Soluble Guanylate Cyclase on Cardiac, Vascular, and Renal Structure and Function: A Physiopathological Insight.International journal of molecular sciences · 2025Review
- The role of mechanosignaling in the control of myocardial mass.American journal of physiology. Heart and circulatory physiology · 2025Review
- Endothelial eNOS deficiency causes podocyte injury through NFAT2 and heparanase in diabetic mice.Scientific reports · 2024Article
- Transcriptomic Insights into the Atrial Fibrillation Susceptibility Locus near theInternational journal of molecular sciences · 2024Article
- Deciphering transcriptional dynamics of cardiac hypertrophy and failure in a chamber-specific manner.Biomolecules & biomedicine · 2023Article
- Review
- The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies.Aging and disease · 2023Article
- The dynamic interplay between cardiac mitochondrial health and myocardial structural remodeling in metabolic heart disease, aging, and heart failure.The journal of cardiovascular aging · 2023Article
- Ca2+/calmodulin-dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model.ESC heart failure · 2022Article
- A structural homology approach to identify potential cross-reactive antibody responses following SARS-CoV-2 infection.Scientific reports · 2022Article
- Physiological and Pathophysiological Effects of C-Type Natriuretic Peptide on the Heart.Biology · 2022Review
- Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino.Frontiers in physiology · 2022Article
41 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.