Chen Lijian, Chen Manli, Du Jian, Wan Lijuan, Zhang Lei, Gu Erwei
Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China; The Key Laboratory of Zoonoses and Pathogen Biology Anhui, Hefei, China.
J Surg Res. 2016 Jun 15;203(2):483-90. doi: 10.1016/j.jss.2016.03.052. Epub 2016 Mar 29.
Hyperglycemia is proposed to be an independent risk factor for cardiovascular morbidity and mortality. Preclinical studies suggest that diabetes mellitus exacerbates myocardial ischemia/reperfusion injury and attenuates the effects of cardioprotective strategies. The cardioprotective effects of postconditioning with the opioid analgesic remifentanil against ischemia/reperfusion injury under the hyperglycemic condition remain contradictory. Therefore, the aim of this study was to investigate the mechanisms by which hyperglycemia affects cardioprotection induced by remifentanil postconditioning.
H9c2 cardiomyoblasts were cultured under the normoglycemic or hyperglycemic condition. Cells were exposed to hypoxia/reoxygenation (H/R) injury followed by hypoxia postconditioning (HPC group) or remifentanil postconditioning (RPC group). Cell viability, injury, and apoptosis were measured after each postconditioning treatment. Activation of endoplasmic reticulum stress (ERS) was analyzed by examining the protein levels of GRP78, CHOP, cleaved caspase-12 and cleaved caspase-3.
RPC significantly increased cell viability and reduced apoptosis in normoglycemic cardiomyoblasts, but not in hyperglycemic cardiomyoblasts. HPC and RPC markedly decreased the upregulation of GRP78, CHOP, cleaved caspase 12, and cleaved caspase 3 in response to H/R injury under the normoglycemic condition. Hyperglycemia significantly increased these ERS-associated biomarkers and apoptosis, which could not be reduced by HPC or RPC.
Remifentanil postconditioning protected cardiomyoblasts from H/R injury under normoglycemia, at least in part, through inhibiting ERS-induced apoptosis. Hyperglycemia attenuated the cardioprotection conferred by remifentanil postconditioning, likely as a result of the exacerbated ERS. Inhibiting the ERS response may be an attractive strategy to enhance the cardioprotective effects of postconditioning in diabetic patients.
高血糖被认为是心血管疾病发病和死亡的独立危险因素。临床前研究表明，糖尿病会加重心肌缺血/再灌注损伤，并减弱心脏保护策略的效果。在高血糖条件下，阿片类镇痛药瑞芬太尼进行后处理对缺血/再灌注损伤的心脏保护作用仍存在争议。因此，本研究的目的是探讨高血糖影响瑞芬太尼后处理诱导的心脏保护作用的机制。
将H9c2心肌细胞在正常血糖或高血糖条件下培养。细胞先经历缺氧/复氧（H/R）损伤，然后进行缺氧后处理（HPC组）或瑞芬太尼后处理（RPC组）。每次后处理后测量细胞活力、损伤和凋亡情况。通过检测GRP78、CHOP、裂解的caspase-12和裂解的caspase-3的蛋白水平来分析内质网应激（ERS）的激活情况。
RPC显著提高了正常血糖心肌细胞中的细胞活力并减少了凋亡，但在高血糖心肌细胞中未观察到这种现象。在正常血糖条件下，HPC和RPC均显著降低了H/R损伤诱导下GRP78、CHOP、裂解的caspase 12和裂解的caspase 3的上调。高血糖显著增加了这些与ERS相关的生物标志物及凋亡，HPC或RPC均无法降低其水平。
瑞芬太尼后处理至少部分通过抑制ERS诱导的凋亡保护正常血糖条件下心肌细胞免受H/R损伤。高血糖减弱了瑞芬太尼后处理带来的心保护作用可能是ERS加剧的结果。抑制ERS反应可能是增强糖尿病患者后处理心脏保护作用的一种有吸引力的策略
