Phosphodiesterase 5 Inhibition Limits Doxorubicin-induced Heart Failure by Attenuating Protein Kinase G Iα Oxidation

Phosphodiesterase 5 (PDE5) inhibitors limit myocardial injury caused by stresses, including doxorubicin chemotherapy. cGMP binding to PKG I ? attenuates oxidant-induced disulfide formation. Because PDE5 inhibition elevates cGMP and pro- tects from doxorubicin-induced injury, we reasoned that this may be because it limits PKG I ? disulfide formation. To inves- tigate the role of PKG I ? disulfide dimerization in the develop- ment of apoptosis, doxorubicin-induced cardiomyopathy was compared in male wild type (WT) or disulfide-resistant C42S PKG I ? 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 WThearts. 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. InWTmice, co-administration of tadalafil with doxorubicin reduced PKG I ? oxidation caused by doxorubicinandalso protected against cardiac injuryandloss of function. KI mice were again innately resistant to doxorubi- cin-induced cardiotoxicity, and therefore tadalafil afforded no additional protection. Doxorubicin decreased phosphorylation of RhoA (Ser-188), stimulating its GTPase activity to activate Rho-associatedproteinkinase(ROCK)inWTs.Thesepro-apopto- tic events were absent in KI mice and were attenuated inWTsco- administered tadalafil.PKGI ? disulfideformationtriggers cardiac injury, and this initiation of maladaptive signaling can be blocked by pharmacological therapies that elevate cGMP, which binds kinase to limit its oxidation.