C1q/TNF-related protein 9 alleviates atherosclerosis by inhibiting ox-LDL-induced VSMC-derived foam cell necroptosis via the AMPK pathway

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.