Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Central Laboratory of The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Int J Mol Med. 2019 Jun;43(6):2451-2461. doi: 10.3892/ijmm.2019.4166. Epub 2019 Apr 15.
Ischemic postconditioning (IPoC) has been demonstrated to prevent myocardial ischemia‑reperfusion injury (MIRI), but its cardioprotective effect is abrogated by hypercholesterolemia. The aim of the present study was to determine whether lycopene (LP), a type of carotenoid, can restore the cardioprotective effect of IPoC in hypercholesterolemic rats. Male Wistar rats were fed a cholesterol‑enriched diet for 12 weeks to establish a hypercholesterolemic model. The rat hearts were isolated and subjected to 30 min ischemia and 60 min reperfusion using a Langendorff apparatus. LP was administered to the rats intraperitoneally for 5 consecutive days prior to ischemia and reperfusion. Myocardial pathological changes, infarct size and cell apoptosis were measured by hematoxylin and eosin, triphenyltetrazolium chloride and TUNEL staining, respectively. The changes in endoplasmic reticulum (ER) stress markers, the reperfusion injury salvage kinase (RISK) pathway and mitochondrial apoptosis‑related proteins were detected by western blotting. Overall, the results demonstrated that low‑dose LP in combination with IPoC ameliorated myocardial histopathological changes, reduced the infarct size and release of cardiac enzymes, and decreased cardiomyocyte apoptosis in hypercholesterolemic rats, but no beneficial effects were achieved by the same dose of LP or IPoC treatment were used alone. Furthermore, the combination of LP and IPoC inhibited the expression of glucose‑regulated protein 78 and C/EBP homologous protein, increased the phosphorylation levels of AKT, ERK1/2 and glycogen synthase kinase‑3β, repressed mitochondrial permeability transition pore opening, and reduced the expression of cytochrome c, cleaved caspase‑9 and cleaved caspase‑3. Collectively, these findings demonstrated that LP can restore the cardioprotective effects of IPoC on MIRI in hypercholesterolemic rats, and this restoration by LP was mediated by inhibition of ER stress and reactivation of the RISK pathway in hypercholesterolemic rat myocardium.
缺血后处理（IPoC）已被证明可预防心肌缺血再灌注损伤（MIRI），但在高胆固醇血症时其心脏保护作用被削弱。本研究旨在确定番茄红素（LP）作为一种类胡萝卜素，是否可以恢复 IPoC 在高胆固醇血症大鼠中的心脏保护作用。雄性 Wistar 大鼠给予富含胆固醇的饮食 12 周，以建立高胆固醇血症模型。使用 Langendorff 装置将大鼠心脏分离并进行 30 分钟缺血和 60 分钟再灌注。LP 通过腹腔内给药，在缺血和再灌注前连续 5 天给药。通过苏木精和伊红、三苯基氯化四氮唑和 TUNEL 染色分别测量心肌病理变化、梗死面积和细胞凋亡。通过 Western blot 检测内质网（ER）应激标志物、再灌注损伤挽救激酶（RISK）途径和线粒体凋亡相关蛋白的变化。总的来说，结果表明，低剂量 LP 与 IPoC 联合应用可改善高胆固醇血症大鼠的心肌组织病理学变化，减少梗死面积和心肌酶的释放，减少心肌细胞凋亡，但相同剂量的 LP 或 IPoC 单独应用均无获益。此外，LP 与 IPoC 的联合应用抑制葡萄糖调节蛋白 78 和 C/EBP 同源蛋白的表达，增加 AKT、ERK1/2 和糖原合酶激酶-3β的磷酸化水平，抑制线粒体通透性转换孔的开放，并降低细胞色素 c、裂解的 caspase-9 和裂解的 caspase-3 的表达。综上所述，这些发现表明，LP 可以恢复 IPoC 对高胆固醇血症大鼠 MIRI 的心脏保护作用，LP 通过抑制 ER 应激和重新激活高胆固醇血症大鼠心肌中的 RISK 途径来实现这种恢复。
