2. Academic Validation
  3. CypD induced ROS output promotes intracranial aneurysm formation and rupture by 8-OHdG/NLRP3/MMP9 pathway

CypD induced ROS output promotes intracranial aneurysm formation and rupture by 8-OHdG/NLRP3/MMP9 pathway

  • Redox Biol. 2023 Sep 12;67:102887. doi: 10.1016/j.redox.2023.102887.
Haiyan Fan 1,  Hao Tian 2,  Fa Jin 2,  Xin Zhang 2,  Shixing Su 2,  Yanchao Liu 2,  Zhuohua Wen 2,  Xuying He 2,  Xifeng Li 3,  Chuanzhi Duan 4
Affiliations

Affiliations

  • 1 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. Electronic address: fan_haiyan2021@163.com.
  • 2 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.
  • 3 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. Electronic address: nflxf@126.com.
  • 4 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; Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Guangzhou, 510280, Guangdong, China. Electronic address: doctor_duanzj@163.com.
PMID: 37717465 DOI: 10.1016/j.redox.2023.102887
Abstract

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.

Keywords

Cyclophilin D; Intracranial aneurysm; Reactive oxygen species; Vascular smooth muscle cell.

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