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Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post?conditioning.

ABSTRACT: Ischemic post?conditioning (IPO) and diazoxide post?conditioning (DPO) has been proven to reduce myocardial ischemia reperfusion injury (MIRI); however, the mechanisms of IPO/DPO are still not clear. The present study aimed to investigate whether mitochondrial ATP?sensitive potassium channels (mitoKATP) channels are activated by IPO/DPO, which may further activate the hypoxia inducible factor 1/hypoxic response element (HIF?1/HRE) pathway to mitigate MIRI. Using a Langendorff perfusion device, healthy male (250?300 g) Sprague Dawley rat hearts were randomly divided into the following groups. Group N was aerobically perfused with K?H solution for 120 min. Group ischaemia/reperfusion (I/R) was aerobically perfused for 20 min, then subjected to 40 min hypoxia plus 60 min reperfusion. Group IPO was treated like the I/R group, but with 10 sec of hypoxia plus 10 sec of reperfusion for six rounds before reperfusion. Group DPO was exposed to 50 µM diazoxide for 5 min before reperfusion and otherwise treated the same as group I/R. In groups IPO+5?hydroxydecanoic acid (5HD), DPO+5HD and I/R+5HD, exposure to 100 µM 5HD (a mitoKATP channel specific blocker) for 5 min before reperfusion as described for groups IPO, DPO and I/R, respectively. In groups IPO+2?methoxyestradiol (2ME2), DPO+2ME2 and I/R+2ME2, exposure to 2 µM 2ME2 (a HIF?1? specific blocker) for 10 min before reperfusion as described for groups IPO, DPO and I/R respectively. Cardiac hemodynamics, myocardial injury and the expression of HIF?1/HRE pathway [HIF?1?, heme oxygenase (HO?1), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF)] were detected in each group. The infarct size and mitochondrial Flameng scores of groups IPO/DPO were significantly decreased compared with the I/R group (P<0.05), but the myocardial protective effects of IPO/DPO could be eliminated by 5HD or 2ME2 (P<0.05). In addition, IPO/DPO could increase the mRNA expression of HIF?1? and the downstream factors of the HIF?1/HRE pathway (the mRNA and protein expression of HO?1, iNOS and VEGF; P<0.05). However, the myocardial protective effects and the activation the HIF?1/HRE pathway mediated by IPO/DPO could be eliminated by 5HD or 2ME2 (P<0.05). Therefore, the activation of the HIF?1/HRE pathway by opening mitoKATP channels may work with the mechanism of IPO/DPO in reducing MIRI.

SUBMITTER: Li J

PROVIDER: S-EPMC7003038 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post‑conditioning.

Li Jin J Zhou Wenjing W Chen Wei W Wang Haiying H Zhang Yu Y Yu Tian T

Molecular medicine reports 20200128 3

Ischemic post‑conditioning (IPO) and diazoxide post‑conditioning (DPO) has been proven to reduce myocardial ischemia reperfusion injury (MIRI); however, the mechanisms of IPO/DPO are still not clear. The present study aimed to investigate whether mitochondrial ATP‑sensitive potassium channels (mitoKATP) channels are activated by IPO/DPO, which may further activate the hypoxia inducible factor 1/hypoxic response element (HIF‑1/HRE) pathway to mitigate MIRI. Using a Langendorff perfusion device, h ...[more]

PMID: 32016463

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Project description:AIMS/INTRODUCTION:Given the high prevalence of diabetes and burn injuries worldwide, it is essential to dissect the underlying mechanism of delayed burn wound healing in diabetes patients, especially the high glucose-induced hypoxia-inducible factor 1 (HIF-1)-mediated transcription defects. MATERIALS AND METHODS:Human umbilical vein endothelial cells were cultured with low or high concentrations of glucose. HIF-1?-induced vascular endothelial growth factor (VEGF) transcription was measured by luciferase assay. Immunofluorescence staining was carried out to visualize cyclic adenosine monophosphate response element binding protein (CREB) localization. Immunoprecipitation was carried out to characterize the association between HIF-1?/p300/CREB. To test whether p300, CREB or p300+CREB co-overexpression was sufficient to rescue the HIF-1-mediated transcription defect after high glucose exposure, p300, CREB or p300+CREB co-overexpression were engineered, and VEGF expression was quantified. Finally, in vitro angiogenesis assay was carried out to test whether the high glucose-induced angiogenesis defect is rescuable by p300 and CREB co-overexpression. RESULTS:Chronic high glucose treatment resulted in impaired HIF-1-induced VEGF transcription and CREB exclusion from the nucleus. P300 or CREB overexpression alone cannot rescue high glucose-induced HIF-1? transcription defects. In contrast, co-overexpression of p300 and CREB dramatically ameliorated high glucose-induced impairment of HIF-1-mediated VEGF transcription, as well as in vitro angiogenesis. Finally, we showed that co-overexpression of p300 and CREB rectifies the dissociation of HIF-1?-p300-CREB protein complex in chronic high glucose-treated cells. CONCLUSION:Both p300 and CREB are required for the function integrity of HIF-1? transcription machinery and subsequent angiogenesis, suggesting future studies to improve burn wound healing might be directed to optimization of the interaction between p300, CREB and HIF-1?.

Dataset Information

Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post?conditioning.

Publications

Mechanism of the hypoxia inducible factor 1/hypoxic response element pathway in rat myocardial ischemia/diazoxide post‑conditioning.

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