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Prevention of PKG1? oxidation augments cardioprotection in the stressed heart.

ABSTRACT: The cGMP-dependent protein kinase-1? (PKG1?) transduces NO and natriuretic peptide signaling; therefore, PKG1? activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1? pathway activation and underlie variable clinical results. PKG1? 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? oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1? 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?(C42S)) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1? altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced PKG1?(C42S) translocated to and remained at the outer plasma membrane. This altered PKG1? localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1? oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1? pathway stimulation in heart disease, and indicate that maintaining PKG1? in its reduced form may optimize its intrinsic cardioprotective properties.

SUBMITTER: Nakamura T

PROVIDER: S-EPMC4497760 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Prevention of PKG1α oxidation augments cardioprotection in the stressed heart.

Nakamura Taishi T Ranek Mark J MJ Lee Dong I DI Shalkey Hahn Virginia V Kim Choel C Eaton Philip P Kass David A DA

The Journal of clinical investigation 20150504 6

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 regulati ...[more]

PMID: 25938783

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Project description:We have previously shown that transplantation of autologously derived, respiration-competent mitochondria by direct injection into the heart following transient ischemia and reperfusion enhances cell viability and contractile function. To increase the therapeutic potential of this approach, we investigated whether exogenous mitochondria can be effectively delivered through the coronary vasculature to protect the ischemic myocardium and studied the fate of these transplanted organelles in the heart. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and then reperfused for 10 minutes. Mitochondria were labeled with 18F-rhodamine 6G and iron oxide nanoparticles. The labeled mitochondria were either directly injected into the ischemic region or delivered by vascular perfusion through the coronary arteries at the onset of reperfusion. These hearts were used for positron emission tomography, microcomputed tomography, and magnetic resonance imaging with subsequent microscopic analyses of tissue sections to confirm the uptake and distribution of exogenous mitochondria. Injected mitochondria were localized near the site of delivery; while, vascular perfusion of mitochondria resulted in rapid and extensive dispersal throughout the heart. Both injected and perfused mitochondria were observed in interstitial spaces and were associated with blood vessels and cardiomyocytes. To determine the efficacy of vascular perfusion of mitochondria, an additional group of rabbit hearts were subjected to 30 minutes of regional ischemia and reperfused for 120 minutes. Immediately following regional ischemia, the hearts received unlabeled, autologous mitochondria delivered through the coronary arteries. Autologous mitochondria perfused through the coronary vasculature significantly decreased infarct size and significantly enhanced post-ischemic myocardial function. In conclusion, the delivery of mitochondria through the coronary arteries resulted in their rapid integration and widespread distribution throughout the heart and provided cardioprotection from ischemia-reperfusion injury.

Dataset Information

Prevention of PKG1? oxidation augments cardioprotection in the stressed heart.

Publications

Prevention of PKG1α oxidation augments cardioprotection in the stressed heart.

Similar Datasets

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