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Hypoxia-inducible factors and the response to hypoxic stress.

ABSTRACT: Oxygen (O(2)) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O(2) availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containing enzymes (PHDs), the HIF? subunits are intricately responsive to numerous other factors, including factor-inhibiting HIF1? (FIH1), sirtuins, and metabolites. These transcription factors function in normal tissue homeostasis and impinge on critical aspects of disease progression and recovery. Insights from basic HIF biology are being translated into pharmaceuticals targeting the HIF pathway.

SUBMITTER: Majmundar AJ

PROVIDER: S-EPMC3143508 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Hypoxia-inducible factors and the response to hypoxic stress.

Majmundar Amar J AJ Wong Waihay J WJ Simon M Celeste MC

Molecular cell 20101001 2

Oxygen (O(2)) is an essential nutrient that serves as a key substrate in cellular metabolism and bioenergetics. In a variety of physiological and pathological states, organisms encounter insufficient O(2) availability, or hypoxia. In order to cope with this stress, evolutionarily conserved responses are engaged. In mammals, the primary transcriptional response to hypoxic stress is mediated by the hypoxia-inducible factors (HIFs). While canonically regulated by prolyl hydroxylase domain-containin ...[more]

PMID: 20965423

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Project description: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‑1α 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‑1α, 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‑1α 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.

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Hypoxia-inducible factors and the response to hypoxic stress.

Publications

Hypoxia-inducible factors and the response to hypoxic stress.

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