| First Author | Nakamura T | Year | 2015 |
| Journal | J Clin Invest | Volume | 125 |
| Issue | 6 | Pages | 2468-72 |
| PubMed ID | 25938783 | Mgi Jnum | J:222967 |
| Mgi Id | MGI:5646090 | Doi | 10.1172/JCI80275 |
| Citation | Nakamura T, et al. (2015) Prevention of PKG1alpha oxidation augments cardioprotection in the stressed heart. J Clin Invest 125(6):2468-72 |
| abstractText | The cGMP-dependent protein kinase-1alpha (PKG1alpha) transduces NO and natriuretic peptide signaling; therefore, PKG1alpha activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1alpha pathway activation and underlie variable clinical results. PKG1alpha can also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, the impact of PKG1alpha oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1alpha 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 (PKG1alpha(C42S)) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1alpha altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced PKG1alpha(C42S) translocated to and remained at the outer plasma membrane. This altered PKG1alpha localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1alpha oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1alpha pathway stimulation in heart disease, and indicate that maintaining PKG1alpha in its reduced form may optimize its intrinsic cardioprotective properties. |
