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

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.

Graphical abstract

The schematic diagram demonstrating that cypD induced ROS output promotes cell apoptosis and elastin degradation through 8-OHDG/NLRP3/MMP9 signaling pathway to accelerate intracranial aneurysm formation and rupture in mice. CypD, Cyclophilin D; CsA, Cyclosporine A; ATP5B, ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide; ROS, Reactive Oxygen Species; 8-OHdG, 8-hydroxy-2 deoxyguanosine; NLRP3, NOD-like receptor thermal protein domain associated protein 3; MMP9, matrix metallopeptidase 9; ECM, Extracellular matrix; VSMC, vascular smooth muscle cell.

Highlights

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  CypD is notably upregulated in IA lesions of human and mice.

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  CypD promotes IA formation and rupture.

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  CypD induced ROS output by binding to ATP5B.

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  8-OHDG/NLRP3/MMP9 pathway is involved in cypD mediated vascular injury.

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  CsA may be efficient for preventing IA progression.