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Prevention of PKG1α oxidation augments cardioprotection in the stressed heart
Taishi Nakamura, … , Philip Eaton, David A. Kass
Taishi Nakamura, … , Philip Eaton, David A. Kass
Published May 4, 2015
Citation Information: J Clin Invest. 2015;125(6):2468-2472. https://doi.org/10.1172/JCI80275.
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Brief Report Cardiology

Prevention of PKG1α oxidation augments cardioprotection in the stressed heart

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Abstract

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.

Authors

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

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Figure 1

PKG1α oxidation at C42 increases in failing and hypertrophied myocardium, and its prevention protects the heart against pressure overload.

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PKG1α oxidation at C42 increases in failing and hypertrophied myocardium...
(A) PKG1α disulfide dimer formation was increased in human heart failure (n = 7–8/group, *P < 0.001). D, PKG1α dimer; HF, heart failure; M, PKG1α monomer; NF, nonfailing. (B) An example of M-mode echocardiograms from PKG1αC42S and littermate controls subjected to TAC and summary data for fractional shortening (n = 9–10, WT sham; n = 17–19, WT TAC; n = 9–10, KI sham; n = 20–23, KI TAC). Sham data were superimposable and thus combined for 2-way ANOVA interaction between TAC and genotype; ANOVA results: *P < 0.005 versus sham and KI TAC; †P < 0.01 versus sham. (C) Histopathology (wheat germ agglutinin [WGA] and Masson’s trichrome) shows larger heart and myocyte size and fibrosis in WT versus PKG1αC42S after TAC. Left ventricular cross-sectional myocyte area and interstitial fibrosis (n = 6, sham; n = 8, TAC). *P < 0.001 versus baseline; †P < 0.01 versus baseline. P values show 2-way ANOVA interaction between TAC and genotype. CSA, cross-sectional area.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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