背景:缺氧是胃粘膜疾病的重要特征,缺氧诱导因子-1α(HIF-1α)有助于微环境紊乱和代谢谱异常。然而,缺氧条件下HIF-1α在胃黏膜损伤中的作用机制及其与线粒体功能障碍的关系尚未完全阐明。
目的:探讨缺氧诱导的HIF-1α在胃黏膜病变发展中的作用。
方法:选择门脉高压性胃病(PHG)和胃癌(GC)作为胃良恶性病变的代表性疾病,分别。收集诊断患有上述疾病的患者的胃组织。在METTL3突变体或NLRP3缺陷型同窝动物中建立门静脉高压症(PHT)诱导的小鼠模型,并建立了具有相关抑制剂的裸鼠胃移植瘤模型。低氧条件的潜在机制,进一步分析了胃粘膜病变的线粒体功能障碍和代谢改变。
结果:HIF-1α,它可以通过上调METTL3/IGF2BP3依赖性动态蛋白相关蛋白1(Drp1)N6-甲基腺苷修饰来介导线粒体功能障碍,以增加线粒体活性氧(mtROS)的产生,在低氧条件下,人和小鼠门脉高压性胃粘膜和GC组织中升高。虽然用PX-478阻断HIF-1α,但通过线粒体分裂抑制剂1(Mdivi-1)治疗或METTL3突变抑制Drp1依赖性线粒体裂变缓解了这一过程。此外,HIF-1α通过乳酸脱氢酶A促进糖酵解影响能量代谢。HIF-1α诱导的Drp1依赖性线粒体裂变也增强了糖酵解。Drp1依赖的线粒体裂变和增强的糖酵解与抗氧化酶活性的改变和线粒体电子传递链的功能障碍有关,导致大规模的MTROS生产,需要激活NLRP3炎性体以加剧PHG和GC的发展。
结论:在低氧条件下,HIF-1α通过依赖Drp1的线粒体裂变增强线粒体功能障碍,并通过改变糖酵解以增加mtROS的产生来影响代谢谱,可以触发NLRP3炎性体激活和粘膜微环境改变,从而促进良性和恶性胃粘膜病变的发展。
Hypoxia is an important characteristic of gastric mucosal diseases, and hypoxia-inducible factor-1α (HIF-1α) contributes to microenvironment disturbance and metabolic spectrum abnormalities. However, the underlying mechanism of HIF-1α and its association with mitochondrial dysfunction in gastric mucosal lesions under hypoxia have not been fully clarified.
To evaluate the effects of hypoxia-induced HIF-1α on the development of gastric mucosal lesions.
Portal hypertensive gastropathy (PHG) and gastric cancer (GC) were selected as representative diseases of benign and malignant gastric lesions, respectively. Gastric tissues from patients diagnosed with the above diseases were collected. Portal hypertension (PHT)-induced mouse models in METTL3 mutant or NLRP3-deficient littermates were established, and nude mouse gastric graft tumour models with relevant inhibitors were generated. The mechanisms underlying hypoxic condition, mitochondrial dysfunction and metabolic alterations in gastric mucosal lesions were further analysed.
HIF-1α, which can mediate mitochondrial dysfunction via upregulation of METTL3/IGF2BP3-dependent dynamin-related protein 1 (Drp1) N6-methyladenosine modification to increase mitochondrial reactive oxygen species (mtROS) production, was elevated under hypoxic conditions in human and mouse portal hypertensive gastric mucosa and GC tissues. While blocking HIF-1α with PX-478, inhibiting Drp1-dependent mitochondrial fission via mitochondrial division inhibitor 1 (Mdivi-1) treatment or METTL3 mutation alleviated this process. Furthermore, HIF-1α influenced energy metabolism by enhancing glycolysis via lactate dehydrogenase A. In addition, HIF-1α-induced Drp1-dependent mitochondrial fission also enhanced glycolysis. Drp1-dependent mitochondrial fission and enhanced glycolysis were associated with alterations in antioxidant enzyme activity and dysfunction of the mitochondrial electron transport chain, resulting in massive mtROS production, which was needed for activation of NLRP3 inflammasome to aggravate the development of the PHG and GC.
Under hypoxic conditions, HIF-1α enhances mitochondrial dysfunction via Drp1-dependent mitochondrial fission and influences the metabolic profile by altering glycolysis to increase mtROS production, which can trigger NLRP3 inflammasome activation and mucosal microenvironment alterations to contribute to the development of benign and malignant gastric mucosal lesions.