Prevention of PKG1α oxidation augments cardioprotection in the stressed heart

The cGMP-dependent protein kinase-1 alpha (PKG1 alpha) transduces NO and natriuretic peptide signaling; therefore, PKG1 alpha activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1 alpha pathway activation and underlie variable clinical results. PKG1 alpha can also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, the impact of PKG1 alpha oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1 alpha 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 (PKG1 alpha(c429) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1 alpha altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced PKG1 alpha(c425) translocated to and remained at the outer plasma membrane. This altered PKG1 alpha localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1 alpha oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1 alpha pathway stimulation in heart disease, and indicate that maintaining PKG1 alpha in its reduced form may optimize its intrinsic cardioprotective properties.