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 (mitoK aTP) 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 mitoK aTP 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 mitoK aTP channels may work with the mechanism of iPo/dPo in reducing Miri.

<p>Dexmedetomidine Attenuates Cellular Injury and Apoptosis in H9c2 Cardiomyocytes by Regulating p-38MAPK and Endoplasmic Reticulum Stress</p>

“…Fortunately, numerous animal studies evaluating diverse protective mechanisms have confirmed the efficacy of cardioprotection in ameliorating MIRI. [1][2][3][4][5][6] The actual clinical application of some of these strategies, however, does not match the animal study applications, and it is difficult to predict the consequences in clinical practice from those seen in experimental research. [7][8][9] In this context, the unclear mechanism underlying the development of apoptotic pathways or involving key molecules in MIRI might significantly matter, especially for cell death and even associated signalling pathways during ischaemia-reperfusion, such as ERS-related apoptosis or signalling pathways; a noteworthy report by Davidson in 2019 shared the opinion that multitarget strategies must be adopted to reduce MIRI if appropriate because single approaches have a limited capacity to overcome complicated MIRI situations.…”

Mitochondrial proteomics alterations in rat hearts following ischemia/reperfusion and diazoxide post‑conditioning

“…Furthermore, the expression levels of certain mitochondrial proteins are altered following myocardial I/R injury and ischemic preconditioning (10)(11)(12). Recently, it was reported that D-Post may protect Langendorff I/R hearts via the mitochondrial ATP-sensitive potassium channel (mitoK ATP ) and the hypoxia-inducible factor-1/hypoxia response element pathway (13).…”

Dexmedetomidine at a dose of 1 µM attenuates H9c2 cardiomyocyte injury under 3 h of hypoxia exposure and 3 h of reoxygenation through the inhibition of endoplasmic reticulum stress

“…Myocardial ischemia-reperfusion injury (MIRI), which usually occurs in clinical settings, leads to severe outcomes for patients if no effective strategies are applied to inhibit the downstream apoptotic cascades. However, numerous animal studies that have revealed various protective mechanisms have also confirmed the efficacy of cardioprotection in overcoming MIRI (1)(2)(3)(4)(5)(6). However, the results achieved in the clinical application of these strategies have not been consistent with those achieved in experimental research (7)(8)(9).…”