BMP‐7 inhibits Pyroptosis in Vascular Smooth Muscle Cells in ATH

Abstract

Atherosclerosis (ATH) is an inflammation‐mediated disease in which lipids, immune cells, and vascular cells contribute to the formation of plaque along vessel walls. Cell death by apoptosis and necrosis have been demonstrated in ATH; however, pyroptosis, an inflammation‐mediated cell death, has not yet been fully elucidated. We hypothesized that pyroptosis of vascular smooth muscle cells contributes to ATH progression. We further investigated whether administration of bone morphogenetic protein‐7 (BMP‐7) can inhibit these effects and demonstrate therapeutic potential. ApoE−/− mice (11±1 week old) were divided into three groups: Sham, PLCA, PLCA+BMP‐7 (200μg/kg; i.v). ATH was generated using our established partial ligation of the left carotid artery (PLCA) model and immunohistochemical staining and western blot analysis of arterial tissue was performed. ATH generated in PLCA mice demonstrated an upregulation in Toll‐like receptor‐4 (TLR‐4) and NLRP3 inflammasome components (NLRP3 and Caspase‐1), indicating the initiation and activation of pyroptosis in vascular smooth muscle (α‐SMA) cells. Further, inflammasome cleavage of pro‐IL‐1β and pro‐IL‐18 to mature forms released through cell membrane pores mediated by Caspase‐11 were investigated. IHC staining of arterial tissue demonstrated a significant increase in IL‐1β and IL‐18 expression following PLCA (p<0.05), which was significantly improved upon treatment with BMP‐7. Western blot analysis of arterial tissue supported these findings, indicating a significant upregulation in pyroptosis initiation via TLR‐4, inflammasome activation (Caspase‐1 and NLRP3) and release of pro‐inflammatory factors, IL‐1β and IL‐18 (p<0.05). Overall, this study indicates that pyroptosis occurs in the vascular smooth muscle cells in ATH and that BMP‐7 administration attenuates pyroptosis significantly.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.