Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Qinghai University, Xining, China.
Research Center for High Altitude Medicine, Key Laboratory of High Altitude Medicine (Ministry of Education), Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Qinghai University, Xining, China; Qinghai Provincial People's Hospital, Xining, Qinghai, China.
Biochem Pharmacol. 2024 Jul;225:116275. doi: 10.1016/j.bcp.2024.116275. Epub 2024 May 8.
Atherosclerosis (AS) is the common pathophysiological basis of various cardiovascular diseases and the leading cause of death from cardiovascular disease worldwide. When the body is in a hypoxic environment, enhanced oxidative stress and significant accumulation of reactive oxygen species (ROS) in tissue cells exacerbate the inflammatory response, resulting in increased release of myeloperoxidase (MPO), catalyzing the formation of large quantities of hypochlorous acid (HOCl), further oxidative modification of low-density lipoprotein (LDL), and exacerbating the formation and progression of atherosclerotic plaques. The MAPK signaling pathway is important in oxidative stress-mediated promotion of atherogenesis. MPO -/- mice were used in this study to establish a hypoxia model simulating 5000 m altitude and a Western high-fat diet-induced atherosclerosis model for 12 weeks. Exploring the role of MPO in the atherosclerotic process in hypoxic mice by observing the MAPK signaling pathway to provide a therapeutic target for the prevention and treatment of hypoxic atherosclerotic disease in the plateau. We found that hypoxia promotes the formation of atherosclerosis in mice, and the mechanism may be that increased MPO in vivo promotes an inflammatory response, which plays a crucial role in the formation of atherosclerosis. In addition, hypoxia further exacerbates plaque instability by activating the MAPK signaling pathway to upregulate vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP9), which in turn promotes angiogenesis within the plaque. Therefore, a potential target for preventing and treating hypoxic atherosclerotic disease is the inhibition of MPO.
动脉粥样硬化（AS）是各种心血管疾病的共同病理生理基础，也是全球心血管疾病死亡的主要原因。当机体处于低氧环境时，氧化应激增强，组织细胞内活性氧（ROS）大量堆积，加剧炎症反应，导致髓过氧化物酶（MPO）大量释放，催化形成大量次氯酸（HOCl），进一步氧化修饰低密度脂蛋白（LDL），加剧动脉粥样硬化斑块的形成和进展。MAPK 信号通路在氧化应激介导的动脉粥样硬化形成中起着重要作用。本研究通过建立模拟海拔 5000m 的低氧模型和 12 周的 Western 高脂饮食诱导的动脉粥样硬化模型，使用 MPO-/-小鼠，观察 MAPK 信号通路，探讨 MPO 在低氧小鼠动脉粥样硬化过程中的作用，为高原低氧性动脉粥样硬化疾病的防治提供治疗靶点。我们发现低氧促进了小鼠动脉粥样硬化的形成，其机制可能是体内 MPO 的增加促进了炎症反应，在动脉粥样硬化的形成中起着关键作用。此外，低氧通过激活 MAPK 信号通路进一步加剧斑块的不稳定性，上调血管内皮生长因子（VEGF）和基质金属蛋白酶-9（MMP9），从而促进斑块内的血管生成。因此，抑制 MPO 可能成为预防和治疗低氧性动脉粥样硬化疾病的潜在靶点。
