ArticleThe Journal of biological chemistry2016
Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 46 citations in OpenAlex.
- Vardenafil Alleviates Doxorubicin-Induced Cardiotoxicity Associated with Restoration of the AMPK/SIRT1 Signaling Pathway.Biomedicines · 2026Article
- Phosphodiesterase-5 Inhibitors as Therapeutics for Cardiovascular Diseases: A Brief Review.Iranian journal of public health · 2023Review
- Ca2+/calmodulin-dependent protein kinase II and protein kinase G oxidation contributes to impaired sarcomeric proteins in hypertrophy model.ESC heart failure · 2022Article
- Detecting Validated Intracellular ROS Generation withMolecular imaging and biology · 2022Article
- The role of activation of two different sGC binding sites by NO-dependent and NO-independent mechanisms in the regulation of SACs in rat ventricular cardiomyocytes.Physiological reports · 2022Article
- Cariporide Attenuates Doxorubicin-Induced Cardiotoxicity in Rats by Inhibiting Oxidative Stress, Inflammation and Apoptosis Partly Through Regulation of Akt/GSK-3β and Sirt1 Signaling Pathway.Frontiers in pharmacology · 2022Article
- Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity.Frontiers in cardiovascular medicine · 2022Review
- Cyclic GMP and PKG Signaling in Heart Failure.Frontiers in pharmacology · 2022Review
- Review
- HCell death discovery · 2021Article
- Role of Phosphodiesterase in the Biology and Pathology of Diabetes.International journal of molecular sciences · 2020Review
- The molecular mechanisms associated with the physiological responses to inflammation and oxidative stress in cardiovascular diseases.Biophysical reviews · 2020Review
- PKG1α Cysteine-42 Redox State Controls mTORC1 Activation in Pathological Cardiac Hypertrophy.Circulation research · 2020Article
- Weighted correlation network bioinformatics uncovers a key molecular biosignature driving the left-sided heart failure.BMC medical genomics · 2020Article
- Osteocrin attenuates inflammation, oxidative stress, apoptosis, and cardiac dysfunction in doxorubicin-induced cardiotoxicity.Clinical and translational medicine · 2020Article
- Serum IgG-induced microglial activation enhances neuronal cytolysis via the NO/sGC/PKG pathway in children with opsoclonus-myoclonus syndrome and neuroblastoma.Journal of neuroinflammation · 2020Article
- Cardiac Cyclic Nucleotide Phosphodiesterases: Roles and Therapeutic Potential in Heart Failure.Cardiovascular drugs and therapy · 2020Review
- cGMP Signaling and Modulation in Heart Failure.Journal of cardiovascular pharmacology · 2020Review
- Remote Ischemic Pre-Conditioning Attenuates Adverse Cardiac Remodeling and Mortality Following Doxorubicin Administration in Mice.JACC. CardioOncology · 2019Article
- Phosphodiesterase 5 Associates With β2 Adrenergic Receptor to Modulate Cardiac Function in Type 2 Diabetic Hearts.Journal of the American Heart Association · 2019Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG Iα attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and protects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG Iα disulfide formation. To investigate the role of PKG Iα disulfide dimerization in the development of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG Iα knock-in (KI) mice. Echocardiography showed that doxorubicin treatment caused loss of myocardial tissue and depressed left ventricular function in WT mice. Doxorubicin also reduced pro-survival signaling and increased apoptosis in WT hearts. In contrast, KI mice were markedly resistant to the dysfunction induced by doxorubicin in WTs. In follow-on experiments the influence of the PDE5 inhibitor tadalafil on the development of doxorubicin-induced cardiomyopathy in WT and KI mice was investigated. In WT mice, co-administration of tadalafil with doxorubicin reduced PKG Iα oxidation caused by doxorubicin and also protected against cardiac injury and loss of function. KI mice were again innately resistant to doxorubicin-induced cardiotoxicity, and therefore tadalafil afforded no additional protection. Doxorubicin decreased phosphorylation of RhoA (Ser-188), stimulating its GTPase activity to activate Rho-associated protein kinase (ROCK) in WTs. These pro-apoptotic events were absent in KI mice and were attenuated in WTs co-administered tadalafil. PKG Iα disulfide formation triggers cardiac injury, and this initiation of maladaptive signaling can be blocked by pharmacological therapies that elevate cGMP, which binds kinase to limit its oxidation.
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Registered trials
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.