Cardiac stress results in several adverse effects, including hypertrophy and pathological remodeling, that lead to heart failure. Activation of the cGMP-dependent kinase PKG1α, which mediates cardiac and vascular function in response to NO and natriuretic peptide signaling, has been shown to suppress detrimental responses to cardiac stress. These beneficial effects have led to the exploration of PKG1α as a potential therapeutic target; however, clinical outcomes have been variable. Taishi Nakamura and colleagues at Johns Hopkins Medical Institutions demonstrate that oxidation of PKG1α in response to cardiac stress contributes to adverse heart remodeling. In patients with ischemic heart failure and rodent heart disease models, PKG1α oxidation was increased compared to controls. In rodent models, expression of a redox-dead form of PKG1α (PKG1αC42S) reduced adverse cardiac remodeling and preserved function in response to cardiac stress. Compared to WT PKG1α, which localized to the cytosol, PKG1αC42S translocated to the plasma membrane of cardiomyocytes and enhanced suppression of transient receptor potential channel 6 (TRPC6), a known mediator of cardiac hypertrophy. The results of this study indicate that oxidation of PKG1α prevents beneficial effects in response to cardiac stress and may explain variable responses to activation of the PKG1α pathway in heart disease. Moreover, these results suggest that strategies to prevent or limit PKG1α oxidation may improve cardioprotection. The accompanying images show neonatal rat cardiomyocytes (NRCMs) expressing either WT PKG1α (left) or PKG1αC42S (right) after stimulation with the Gq agonist ET1. Endogenous PKG1α (green) was diffuse in WT PKG1α-expressing NRCMs but localized to the plasma membrane in PKG1αC42S-expressing NRCMs. Note the reduced hypertrophy in PKG1αC42S-expressing NRCMs.
The cGMP-dependent protein kinase-1α (PKG1α) transduces NO and natriuretic peptide signaling; therefore, PKG1α activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1α pathway activation and underlie variable clinical results. PKG1α can also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, the impact of PKG1α oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1α is oxidized in both patients with heart disease and in rodent disease models. Moreover, this oxidation contributed to adverse heart remodeling following sustained pressure overload or Gq agonist stimulation. Compared with control hearts and myocytes, those expressing a redox-dead protein (PKG1αC42S) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1α altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced PKG1αC42S translocated to and remained at the outer plasma membrane. This altered PKG1α localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1α oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1α pathway stimulation in heart disease, and indicate that maintaining PKG1α in its reduced form may optimize its intrinsic cardioprotective properties.
Taishi Nakamura, Mark J. Ranek, Dong I. Lee, Virginia Shalkey Hahn, Choel Kim, Philip Eaton, David A. Kass