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Ube2s-stabilized ?-catenin protects against myocardial ischemia/reperfusion injury by activating HIF-1? signaling.

ABSTRACT: The activation of hypoxia-inducible factor (HIF) is an important event for mediating the adaptive response to myocardial ischemia/reperfusion (MI/R) injury. The ubiquitin-conjugating enzyme E2S (Ube2s) catalyzes ubiquitin conjugation to target proteins. Here, we report the positive regulation of HIF-1? signaling by Ube2s via stabilizing ?-catenin, by which Ube2s acts to protect against MI/R injury. We show that Ube2s expression is upregulated in the hearts of mice subjected to MI/R injury. Functionally, Ube2s depletion exacerbates and its overexpression ameliorates MI/R injury. In addition, Ube2s augments the activation of HIF-1? and reduces myocardial apoptosis. Moreover, Ube2s induces the accumulation of ?-Catenin through increasing its stabilization. Importantly, ?-Catenin knockdown abrogates Ube2s-augmented HIF-1? activation, and meanwhile, diminishes the protective effect of Ube2s on MI/R injury, thus establishing a causal link between Ube2s-stabilized ?-catenin and HIF-1?-mediated myocardial protection. Altogether, this study identifies the Ube2s/?-catenin/HIF-1? axis as a novel protective regulator involved in MI/R injury, and also implies that it might represent a potential therapeutic target for ameliorating MI/R injury.

SUBMITTER: Chen X

PROVIDER: S-EPMC7185123 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Ube2s-stabilized β-catenin protects against myocardial ischemia/reperfusion injury by activating HIF-1α signaling.

Chen Xi X Wang Chiyao C Yang Pei P Shi Lei L Wang Haiyan H

Aging 20200406 7

The activation of hypoxia-inducible factor (HIF) is an important event for mediating the adaptive response to myocardial ischemia/reperfusion (MI/R) injury. The ubiquitin-conjugating enzyme E2S (Ube2s) catalyzes ubiquitin conjugation to target proteins. Here, we report the positive regulation of HIF-1α signaling by Ube2s via stabilizing β-catenin, by which Ube2s acts to protect against MI/R injury. We show that Ube2s expression is upregulated in the hearts of mice subjected to MI/R injury. Funct ...[more]

PMID: 32250966

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Project description:Background:Oxidative stress is a major contributor to the onset and development of myocardial ischemia reperfusion injury (MIRI). Sappanone A (SA), a homoisoflavanone extracted from the heartwood of Caesalpinia sappan L., has been demonstrated to possess powerful antioxidant activity. Therefore, this study aimed to determine the protective effect of SA on MIRI and investigate its underlying mechanism. Methods:The rat hearts were isolated and underwent 30-min ischemia, followed by 120-min reperfusion to establish the MIRI model, using the Langendorff method. SA was administrated intraperitoneally into rats 1 h prior to heart isolation. The myocardial infarct size and apoptosis were measured by TTC and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Myocardial enzyme activity, MDA content and the activities of SOD and GSH-Px were detected by colorimetric spectrophotometric method. Reactive oxygen species (ROS) level was detected by DCFH-DA probe. The change in Keap1/Nrf2 signaling pathway was evaluated by Western blotting. Results:SA reduced myocardial infarct size and the release of CK-MB and LDH in a dose-dependent manner. Moreover, SA improved the recovery of cardiac function, inhibited MIRI-induced apoptosis, repressed the production of ROS and MDA, and enhanced the activities of SOD and GSH-Px. Mechanistically, SA downregulated Keap1, induced Nrf2 nuclear accumulation, and enhanced Nrf2 transcriptional activity, subsequently resulting in an increase in the expression of the Nrf2 target genes heme oxygenase-1 and NAD(P)H quinone dehydrogenase 1. Moreover, SA enhanced the phosphorylation of Nfr2, but the enhancement in Nfr2 phosphorylation was abrogated by PKC or PI3K inhibitor. Conclusion:Collectively, it was demonstrated that SA prevents MIRI via coordinating the cellular antioxidant defenses and maintaining the redox balance, by modulation of Nrf2 via the PKC or PI3K pathway. Therefore, SA was a potential therapeutic drug for treating MIRI.

Dataset Information

Ube2s-stabilized ?-catenin protects against myocardial ischemia/reperfusion injury by activating HIF-1? signaling.

Publications

Ube2s-stabilized β-catenin protects against myocardial ischemia/reperfusion injury by activating HIF-1α signaling.

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