Li Linxia, Liu Yanqi, Zhi Na, Ji Yaoxuan, Xu Jialing, Mao Guoyun, Wang Yazhou, Ma Jin, Wang Yunying
Department of Aerospace Medicine, Air Force Medical University, 710032, Xi'an, China.
Department of Neurobiology and Institute of Neurosciences, Air Force Medical University, 710032, Xi'an, China.
Cell Death Discov. 2024 Apr 4;10(1):164. doi: 10.1038/s41420-024-01937-0.
Hypoxic preconditioning (HPC) has been shown to improve organ tolerance to subsequent severe hypoxia or ischemia. However, its impact on intestinal ischemic injury has not been well studied. In this study, we evaluated the effects of HPC on intestinal ischemia in rats. Intestinal rehabilitation, levels of fatty acid oxidation (FAO) by-products, intestinal stem cells (ISCs), levels of hypoxia-inducible factor 1 subunit α (HIF-1α) and its downstream genes such as peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyltransferase 1a (CPT1A) were assessed at distinct time intervals following intestinal ischemia with or without the interference of HIF-1α. Our data showed that HPC facilitates the restoration of the intestinal structure and enhances the FAO, by boosting intestinal stem cells. Additionally, HIF-1α, PPARα, and CPT1A mRNA and their protein levels were generally up-regulated in the small intestine of HPC rats as compared to the control group. Our vitro experiment also shows low-oxygen induces highly levels of HIF-1α and its downstream genes, with a concurrent increase in FAO products in IEC-6 cells. Furthermore, the above phenomenon could be reversed by silencing HIF-1α. In conclusion, we hypothesize that HPC can stimulate the activation of intestinal stem cells via HIF-1α/PPARα pathway-mediated FAO, thereby accelerating the healing process post ischemic intestinal injury.
缺氧预处理（HPC）已被证明可提高器官对随后严重缺氧或缺血的耐受性。然而，其对肠道缺血性损伤的影响尚未得到充分研究。在本研究中，我们评估了HPC对大鼠肠道缺血的影响。在有或无缺氧诱导因子1亚基α（HIF-1α）干扰的情况下，于肠道缺血后的不同时间间隔评估肠道修复情况、脂肪酸氧化（FAO）副产物水平、肠道干细胞（ISC）、HIF-1α及其下游基因如过氧化物酶体增殖物激活受体α（PPARα）和肉碱棕榈酰转移酶1a（CPT1A）的水平。我们的数据表明，HPC通过促进肠道干细胞来促进肠道结构的恢复并增强FAO。此外，与对照组相比，HPC大鼠小肠中HIF-1α、PPARα和CPT1A的mRNA及其蛋白水平普遍上调。我们的体外实验还表明，低氧可诱导IEC-6细胞中高水平的HIF-1α及其下游基因，同时FAO产物增加。此外，通过沉默HIF-1α可逆转上述现象。总之，我们假设HPC可通过HIF-1α/PPARα途径介导的FAO刺激肠道干细胞的激活，从而加速缺血性肠损伤后的愈合过程。
