title: Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation.
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.
authors.affiliation: From the Rayne Institute and.
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Prysyazhna
authors.affiliation: From the Rayne Institute and.
authors.forename: Joseph Robert
authors.initials: JR
authors.lastname: Burgoyne
authors.affiliation: From the Rayne Institute and.
authors.forename: Jenna
authors.initials: J
authors.lastname: Scotcher
authors.affiliation: the Academic Department of Surgery, King's College London, Cardiovascular Division, British Heart Foundation Centre of Excellence, St. Thomas' Hospital, London, SE1 7EH, United Kingdom and.
authors.forename: Steven
authors.initials: S
authors.lastname: Grover
authors.affiliation: the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205.
authors.forename: David
authors.initials: D
authors.lastname: Kass
authors.affiliation: From the Rayne Institute and philip.eaton@kcl.ac.uk.
authors.forename: Philip
authors.initials: P
authors.lastname: Eaton
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism*; D004317:Doxorubicin / Q000009:adverse effects / Q000494:pharmacology; D006333:Heart Failure / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D015290:Second Messenger Systems / Q000187:drug effects / Q000235:genetics; D000068581:Tadalafil / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D004220:Disulfides; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D004317:Doxorubicin; D054460:rho-Associated Kinases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse; D006152:Cyclic GMP
keywords: apoptosis; cardiomyopathy; heart failure; oxidative stress; phosphodiesterases; protein kinase G (PKG)