Department of Cerebrovascular Surgery, Neurosurgery Center, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China.
Department of Cerebrovascular Surgery, Neurosurgery Center, Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, Guangdong, China.
Redox Biol. 2023 Nov;67:102887. doi: 10.1016/j.redox.2023.102887. Epub 2023 Sep 12.
Reactive Oxygen Species (ROS) are widely accepted as a pernicious factor in the progression of intracranial aneurysm (IA), which is eminently related to cell apoptosis and extracellular matrix degradation, but the mechanism remains to be elucidated. Recent evidence has identified that enhancement of Cyclophilin D (CypD) under stress conditions plays a critical role in ROS output, thus accelerating vascular destruction. However, no study has confirmed whether cypD is a detrimental mediator of cell apoptosis and extracellular matrix degradation in the setting of IA development. Our data indicated that endogenous cypD mRNA was significantly upregulated in human IA lesions and mouse IA wall, accompanied by higher level of ROS, MMPs and cell apoptosis. CypD remarkably reversed vascular smooth muscle cells (VSMCs) apoptosis and elastic fiber degradation, and significantly decreased the incidence of aneurysm and ruptured aneurysm, together with the downregulation of ROS, 8-OHdG, NLRP3 and MMP9 in vivo and vitro. Furthermore, we demonstrated that blockade of cypD with CsA inhibited the above processes, thus preventing IA formation and rupture, these effects were highly dependent on ROS output. Mechanistically, we found that cypD directly interacts with ATP5B to promote ROS release in VSMCs, and 8-OHdG directly bind to NLRP3, which interacted with MMP9 to increased MMP9 level and activity in vivo and vitro. Our data expound an unexpected role of cypD in IA pathogenesis and an undescribed 8-OHdG/NLRP3/MMP9 pathway involved in accelerating VSMCs apoptosis and elastic fiber degradation. Repressing ROS output by CypD inhibition may be a promising therapeutic strategy for prevention IA development.
活性氧 (ROS) 被广泛认为是颅内动脉瘤 (IA) 进展的有害因素，这与细胞凋亡和细胞外基质降解密切相关，但机制尚不清楚。最近的证据表明，应激条件下环孢素 D (CypD) 的增强在 ROS 输出中起关键作用，从而加速血管破坏。然而，尚无研究证实 cypD 是否是 IA 发展过程中细胞凋亡和细胞外基质降解的有害介质。我们的数据表明，内源性 cypD mRNA 在人 IA 病变和小鼠 IA 壁中显著上调，同时伴有 ROS、MMPs 和细胞凋亡水平升高。CypD 显著逆转了血管平滑肌细胞 (VSMCs) 的凋亡和弹性纤维降解，并显著降低了动脉瘤和破裂性动脉瘤的发生率，同时下调了体内和体外的 ROS、8-OHdG、NLRP3 和 MMP9。此外，我们证明 CsA 抑制 cypD 可抑制上述过程，从而防止 IA 的形成和破裂，这些作用高度依赖于 ROS 的输出。在机制上，我们发现 cypD 可直接与 ATP5B 相互作用，促进 VSMCs 中 ROS 的释放，8-OHdG 可直接与 NLRP3 结合，后者与 MMP9 相互作用，增加 MMP9 水平和活性。我们的数据阐述了 cypD 在 IA 发病机制中的意外作用以及 8-OHdG/NLRP3/MMP9 途径在加速 VSMCs 凋亡和弹性纤维降解中的作用。抑制 CypD 抑制 ROS 输出可能是预防 IA 发展的一种有前途的治疗策略。
