Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
Central Laboratory, The Fifth Central Hospital of Tianjin, Tianjin 300450, P.R. China.
Mol Med Rep. 2021 Jun;23(6). doi: 10.3892/mmr.2021.12115. Epub 2021 Apr 26.
Different degrees of myocardial ischemia‑reperfusion injury during open‑heart surgery are inevitable. Therapeutic hypothermia is an important technique for reducing ischemia‑reperfusion injury; however, there are numerous potential adverse effects. Furthermore, the underlying molecular mechanisms of action of therapeutic hypothermia remain unclear. In the present study, rat hearts were perfused for 30 min and subjected to 30 min of regional ischemia, followed by 120 min of reperfusion. Animals received intraperitoneal injection of spectomycin B1 at 30 min prior to the start of surgery. Total myocardial area, infarct area, myocardial injury, and apoptosis were assessed. H9C2 cells were incubated for 24 h at 34˚C with 5% CO to simulate therapeutic hypothermic stress, and cell viability and mitochondrial injury were evaluated. The levels of protein SUMOylation, hypoxia‑inducible factor (HIF)‑1α and vascular endothelial growth factor (VEGF) were determined by western blot analysis. It was demonstrated that hypoxia significantly increased the overall modification by the small ubiquitin‑related modifier protein (SUMO) of various proteins in cardiomyocytes, both and . In turn, this increased the protein levels of HIF‑1α, continuously stimulated downstream VEGF expression. Therapeutic hypothermia further increased protein SUMOylation, whereas inhibiting the SUMOylation pathway reduced the protective effect of therapeutic hypothermia on hypoxic cardiomyocytes. Overall, these data suggested that increasing SUMOylation of HIF‑1α may be an important molecular mechanism underlying the protective effects of therapeutic hypothermia following hypoxia in myocardial cells. These findings may aid in the use of therapeutic hypothermia for treatment of myocardial ischemia‑reperfusion and help avoid excessive side effects.
在心脏直视手术中，不可避免地会出现不同程度的心肌缺血再灌注损伤。治疗性低温是减少缺血再灌注损伤的重要技术；然而，存在许多潜在的不良反应。此外，治疗性低温的作用的潜在分子机制仍不清楚。在本研究中，大鼠心脏灌注 30 分钟，然后进行 30 分钟的区域性缺血，再进行 120 分钟的再灌注。动物在手术开始前 30 分钟接受腹腔注射壮观霉素 B1。评估总心肌面积、梗死面积、心肌损伤和细胞凋亡。H9C2 细胞在 34°C 下孵育 24 小时，5%CO 模拟治疗性低温应激，评估细胞活力和线粒体损伤。通过 Western blot 分析测定蛋白质 SUMO 化、缺氧诱导因子 (HIF) -1α 和血管内皮生长因子 (VEGF) 的水平。结果表明，缺氧显著增加了心肌细胞中各种蛋白质的小泛素相关修饰蛋白 (SUMO) 的整体修饰，无论是 和 。反过来，这增加了 HIF-1α 的蛋白水平，持续刺激下游 VEGF 的表达。治疗性低温进一步增加了蛋白质 SUMO 化，而抑制 SUMO 化途径则降低了治疗性低温对缺氧心肌细胞的保护作用。总体而言，这些数据表明，增加 HIF-1α 的 SUMO 化可能是治疗性低温在心肌细胞缺氧后发挥保护作用的重要分子机制。这些发现可能有助于治疗性低温治疗心肌缺血再灌注，并有助于避免过度的副作用。
