She Han, Zheng Jie, Zhao Guozhi, Du Yunxia, Tan Lei, Chen Zhe-Sheng, Wu Yinyu, Li Yong, Liu Yiyan, Sun Yue, Hu Yi, Zuo Deyu, Mao Qingxiang, Liu Liangming, Li Tao
Department of Anesthesiology, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Shock and Transfusion Department, Daping Hospital, Army Medical University, Chongqing, 400042, China.
Signal Transduct Target Ther. 2025 May 28;10(1):167. doi: 10.1038/s41392-025-02255-2.
Ischemic/hypoxic injury significantly damages vascular function, detrimentally impacting patient outcomes. Changes in mitochondrial structure and function are closely associated with ischemia/hypoxia-induced vascular dysfunction. The mechanism of this process remains elusive. Using rat models of ischemia and hypoxic vascular smooth muscle cells (VSMCs), we combined transmission electron microscopy, super-resolution microscopy, and metabolic analysis to analyze the structure and function change of mitochondrial cristae. Multi-omics approaches revealed arginase 1 (Arg1) upregulation in ischemic VSMCs, confirmed by in vivo and in vitro knockout models showing Arg1's protective effects on mitochondrial cristae, mitochondrial and vascular function, and limited the release of mtDNA. Mechanistically, Arg1 interacting with Mic10 led to mitochondrial cristae remodeling, together with hypoxia-induced VDAC1 lactylation resulting in the opening of MPTP and release of mtDNA of VSMCs. The released mtDNA led to PANoptosis of VSMCs via activation of the cGAS-STING pathway. ChIP-qPCR results demonstrated that lactate-mediated Arg1 up-regulation was due to H3K18la upregulation. VSMCs targeted nano-material PLGA-PEI-siRNA@PM-α-SMA (NP-siArg1) significantly improved vascular dysfunction. This study uncovers a new mechanism of vascular dysfunction following ischemic/hypoxic injury: a damaging positive feedback loop mediated by lactate-regulated Arg1 expression between the nucleus and mitochondria, leading to mitochondria cristae disorder and mtDNA release, culminating in VSMCs PANoptosis. Targeting VSMCs Arg1 inhibition offers a potential therapeutic strategy to alleviate ischemia/hypoxia-induced vascular impairments.
缺血/缺氧损伤会严重损害血管功能，对患者预后产生不利影响。线粒体结构和功能的变化与缺血/缺氧诱导的血管功能障碍密切相关。这一过程的机制仍不清楚。我们使用缺血大鼠模型和缺氧血管平滑肌细胞（VSMCs），结合透射电子显微镜、超分辨率显微镜和代谢分析，来分析线粒体嵴的结构和功能变化。多组学方法揭示了缺血VSMCs中精氨酸酶1（Arg1）上调，体内和体外基因敲除模型证实了Arg1对线粒体嵴、线粒体和血管功能具有保护作用，并限制了线粒体DNA（mtDNA）的释放。从机制上讲，Arg1与Mic10相互作用导致线粒体嵴重塑，同时缺氧诱导的电压依赖性阴离子通道1（VDAC1）乳酰化导致线粒体通透性转换孔（MPTP）开放和VSMCs的mtDNA释放。释放的mtDNA通过激活环鸟苷酸-腺苷酸合成酶-干扰素基因刺激蛋白（cGAS-STING）途径导致VSMCs全程序死亡。染色质免疫沉淀定量聚合酶链反应（ChIP-qPCR）结果表明，乳酸介导的Arg1上调是由于组蛋白H3赖氨酸18乳酸化（H3K18la）上调所致。靶向VSMCs的纳米材料聚乳酸-聚乙烯亚胺-小干扰RNA@血小板源性生长因子α链（NP-siArg1）显著改善了血管功能障碍。本研究揭示了缺血/缺氧损伤后血管功能障碍的新机制：由乳酸调节的细胞核与线粒体之间Arg1表达介导的有害正反馈回路，导致线粒体嵴紊乱和mtDNA释放，最终导致VSMCs全程序死亡。靶向抑制VSMCs的Arg1为减轻缺血/缺氧诱导的血管损伤提供了一种潜在的治疗策略。
