Zhu Ji, Chen Hang, Guo Jianan, Zha Chen, Lu Dezhao
The Third Affiliated Hospital of Zhejiang Chinese Medical University (Zhongshan Hospital of Zhejiang Province), Hangzhou, People's Republic of China.
School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, People's Republic of China.
J Inflamm Res. 2022 Nov 14;15:6293-6306. doi: 10.2147/JIR.S386470. eCollection 2022.
Atherosclerosis (AS) is the underlying cause of cardiovascular events. Endothelial cell mitochondrial damage and pyroptosis are important factors contributing to AS. Changes in internal mitochondrial conformation and increase in reactive oxygen species (ROS) lead to the disruption of mitochondrial energy metabolism, activation of the NLRP3 inflammasome and pyroptosis, which in turn affect atherogenesis by impairing endothelial function. AMPK is a core player in the regulation of cellular metabolism, not only by regulating mitochondrial homeostasis but also by regulating cellular inflammatory responses. Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, has significant antioxidant and anti-inflammatory effects, and roles in cardiovascular protection.
In this study, we investigated whether STS plays a protective role in AS by regulating endothelial cell mitochondrial function and pyroptosis through an AMPK-dependent mitochondrial pathway.
Male ApoE mice and HUVECs were used for the experiments. We found that STS treatment largely abrogated the upregulation of key proteins in aortic vessel wall plaques and typical pyroptosis signaling in ApoE mice fed a western diet, consequently enhancing pAMPK expression, plaque stabilization, and anti-inflammatory responses. Consistently, STS pretreatment inhibited cholesterol crystallization (CC) -induced cell pyroptosis and activated pAMPK expression. In vitro, using HUVECs, we further found that STS treatment ameliorated mitochondrial ROS caused by CC, as evidenced by the finding that STS inhibited mitochondrial damage caused by CC. The improvement of endothelial cell mitochondrial function by STS is blocked by dorsomorphin (AMPK inhibitor). Consistently, the blockade of endothelial cell pyroptosis by STS is disrupted by dorsomorphin.
Our results suggest that STS enhances maintenance of mitochondrial homeostasis and inhibits mitochondrial ROS overproduction via AMPK, thereby improving endothelial cell pyroptosis during AS.
动脉粥样硬化（AS）是心血管事件的根本原因。内皮细胞线粒体损伤和细胞焦亡是导致AS的重要因素。线粒体内在构象的改变和活性氧（ROS）的增加导致线粒体能量代谢紊乱、NLRP3炎性小体激活和细胞焦亡，进而通过损害内皮功能影响动脉粥样硬化的发生发展。AMPK是细胞代谢调节的核心参与者，不仅通过调节线粒体稳态，还通过调节细胞炎症反应发挥作用。丹参酮IIA磺酸钠（STS）是丹参酮IIA的水溶性衍生物，具有显著的抗氧化和抗炎作用，在心血管保护中发挥作用。
在本研究中，我们探讨了STS是否通过依赖AMPK的线粒体途径调节内皮细胞线粒体功能和细胞焦亡，从而在AS中发挥保护作用。
使用雄性ApoE小鼠和人脐静脉内皮细胞（HUVECs）进行实验。我们发现，STS处理在很大程度上消除了喂食西式饮食的ApoE小鼠主动脉血管壁斑块中关键蛋白的上调和典型的细胞焦亡信号，从而增强了pAMPK表达、斑块稳定性和抗炎反应。同样，STS预处理抑制了胆固醇结晶（CC）诱导的细胞焦亡并激活了pAMPK表达。在体外，使用HUVECs，我们进一步发现STS处理改善了CC引起的线粒体ROS，这一发现证明STS抑制了CC引起的线粒体损伤。背侧吗啡（AMPK抑制剂）阻断了STS对内皮细胞线粒体功能的改善。同样，背侧吗啡破坏了STS对内皮细胞焦亡的阻断作用。
我们的结果表明，STS通过AMPK增强线粒体稳态的维持并抑制线粒体ROS的过度产生，从而改善AS期间的内皮细胞焦亡。
