C1q/TNF-related protein 9 alleviates atherosclerosis by inhibiting
ox-LDL-induced VSMC-derived foam cell necroptosis via the AMPK pathway
Abstract
Background and purpose: Necroptosis amplifies inflammation and plays an
important role in atherosclerosis progression. However, the role of
necroptosis of vascular smooth muscle cell (VSMC)-derived foam cells in
atherosclerosis remains unknown. In the present study, we evaluated the
effect of oxidized low-density lipoprotein (ox-LDL) on VSMC-derived foam
cell necroptosis. Furthermore, we determined whether and how
C1q/TNF-related protein 9 (CTRP9), a cardiovascular protective
adipokine, protects against ox-LDL-induced cell dysfunction and
atherosclerosis. Experimental approach: The VSMC-derived foam cell were
established followed by incubation with ox-LDL and Tempol, CTRP9 and
Compound C for 24 h. Cell death was detected by the mtROS levels and
ΔΨm, and the cellular inflammation was tested by the expression of
inflammatory factors. Transmission electron microscopy and flow
cytometry were used to confirm the occurrence of Necroptosis. Western
blotting was used to detect the expression of necroptosis-related
proteins and antioxidant enzymes. In vivo, adeno-associated virus (AAV)
was used to construct an animal model of CTRP9 overexpression. Then the
stability and necroptosis of aortic sinus plaque were detected. Key
Results: Our results revealed that ox-LDL potently induced VSMC-derived
foam cell necroptosis and promoted the expression of pro-atherosclerotic
factors via an oxidative stress-related mechanism. CTRP9 significantly
reversed ox-LDL-induced cell damage and the related dysfunction through
the AMPK pathway-mediated expression of antioxidant enzymes. CTRP9
overexpression reduced atherosclerotic lesion size in the aortic sinus
and enhanced features of plaque stability. Conclusions & Implications:
Overall, our findings suggest that CTRP9 is a potential drug target to
suppress atherosclerosis and stabilize plaques.