ArticleThe Journal of biological chemistry2008
Protein kinase G-dependent cardioprotective mechanism of phosphodiesterase-5 inhibition involves phosphorylation of ERK and GSK3beta.
Article in The Journal of biological chemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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Who cites it
110 citing papers in PubMed, 196 citations in OpenAlex.
- Mitochondrial potassium channels: mitochondria-specific mechanism of regulation.Biophysical reviews · 2026Review
- Comparison of plasma metabolic profiling between children with hypertrophic obstructive cardiomyopathy and healthy controls.Cardiovascular endocrinology & metabolism · 2025Article
- Methylated Arginine Metabolites as Biomarkers for Clinical Status and Response to Type 5 Phosphodiesterase Inhibition in Patients With Fontan Circulation.Journal of the American Heart Association · 2025Article
- C-type natriuretic peptide/cGMP/FoxO3 signaling attenuates hyperproliferation of pericytes from patients with pulmonary arterial hypertension.Communications biology · 2024Article
- PDE10A Inactivation Prevents Doxorubicin-Induced Cardiotoxicity and Tumor Growth.Circulation research · 2023Article
- Phosphodiesterase-5 Inhibitors as Therapeutics for Cardiovascular Diseases: A Brief Review.Iranian journal of public health · 2023Review
- Androgen-deprivation therapy with leuprolide increases abdominal adiposity without causing cardiac dysfunction in middle-aged male mice: effect of sildenafil.American journal of physiology. Regulatory, integrative and comparative physiology · 2023Article
- CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling.JCI insight · 2023Article
- Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways.Frontiers in physiology · 2023Article
- The effect of cardioplegic supplementation with sildenafil on cardiac energetics in a piglet model of cardiopulmonary bypass and cardioplegic arrest with warm or cold cardioplegia.Frontiers in cardiovascular medicine · 2023Article
- How do phosphodiesterase-5 inhibitors affect cancer? A focus on glioblastoma multiforme.Pharmacological reports : PR · 2022Review
- Lavender protects H9c2 cardiomyocytes against oxygen-glucose deprivation (OGD)-induced injury via targeting the JAK2/STAT3 pathway.Iranian journal of basic medical sciences · 2022Article
- Mediation of the Cardioprotective Effects of Mannitol Discovered, with Refutation of Common Protein Kinases.International journal of molecular sciences · 2021Article
- Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities.Pharmacology & therapeutics · 2021Review
- The cGMP system in normal and degenerating mouse neuroretina: New proteins with cGMP interaction potential identified by a proteomics approach.Journal of neurochemistry · 2021Article
- STAT3-miR-17/20 signalling axis plays a critical role in attenuating myocardial infarction following rapamycin treatment in diabetic mice.Cardiovascular research · 2020Article
- Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases.International journal of molecular sciences · 2020Review
- PDE5 inhibitor sildenafil attenuates cardiac microRNA 214 upregulation and pro-apoptotic signaling after chronic alcohol ingestion in mice.Molecular and cellular biochemistry · 2020Article
- Cardiovascular risks and toxicity - The Achilles heel of androgen deprivation therapy in prostate cancer patients.Biochimica et biophysica acta. Reviews on cancer · 2020Review
- Protective Mechanisms of Suxiao Jiuxin Pills () on Myocardial Ischemia-Reperfusion Injury in vivo and in vitro.Chinese journal of integrative medicine · 2020Article
50 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Sildenafil, a potent inhibitor of phosphodiesterase-5 (PDE-5) induces powerful protection against myocardial ischemia-reperfusion injury. PDE-5 inhibition increases cGMP levels that activate cGMP-dependent protein kinase (PKG). However, the cause and effect relationship of PKG in sildenafil-induced cardioprotection and the downstream targets of PKG remain unclear. Adult ventricular myocytes were treated with sildenafil and subjected to simulated ischemia and reoxygenation. Sildenafil treatment significantly decreased cardiomyocyte necrosis and apoptosis. The PKG inhibitors, KT5823, guanosine 3',5'-cyclic monophosphorothioate, 8-(4-chloro-phenylthio) (R(p)-8-pCPT-cGMPs), or DT-2 blocked the anti-necrotic and anti-apoptotic effect of sildenafil. Selective knockdown of PKG in cardiomyocytes with adenoviral vector containing short hairpin RNA of PKG also abolished sildenafil-induced protection. Furthermore, intra-coronary infusion of sildenafil in Langendorff-isolated mouse hearts prior to ischemia-reperfusion significantly reduced myocardial infarct size after 20 min ischemia and 30 min reperfusion, which was abrogated by KT5823. Sildenafil significantly increased PKG activity in intact hearts and cardiomyocytes. Sildenafil also enhanced the Bcl-2/Bax ratio, phosphorylation of Akt, ERK1/2, and glycogen synthase kinase 3beta. All these changes (except Akt phosphorylation) were significantly blocked by KT5823 and short hairpin RNA of PKG. These studies provide the first evidence for an essential role of PKG in sildenafil-induced cardioprotection. Moreover, our results demonstrate that sildenafil activates a PKG-dependent novel signaling cascade that involves activation of ERK and inhibition of glycogen synthase kinase 3beta leading to cytoprotection.
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