Prevention of PKG1a oxidation augments cardioprotection in the stressed heart

Taishi Nakamura, Mark J. Ranek, Dong I. Lee, Virginia Shalkey Hahn, Choel Kim, Philip Eaton, David A. Kass

Research output: Contribution to journalArticlepeer-review

Abstract

The cGMP-dependent protein kinase-1a (PKG1a) transduces NO and natriuretic peptide signaling; therefore, PKG1a activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1a pathway activation and underlie variable clinical results. PKG1a can also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, the impact of PKG1a oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1a 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 (PKG1aC42S) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1a altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced PKG1aC42S translocated to and remained at the outer plasma membrane. This altered PKG1a localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1a oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1a pathway stimulation in heart disease, and indicate that maintaining PKG1a in its reduced form may optimize its intrinsic cardioprotective properties.

Original languageEnglish (US)
Pages (from-to)2468-2472
Number of pages5
JournalJournal of Clinical Investigation
Volume125
Issue number6
DOIs
StatePublished - Jun 1 2015

ASJC Scopus subject areas

  • Medicine(all)

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