Atherosclerosis (ATH) is an inflammation-mediated disease in which cell death underlies the formation of lesions along the intima layer of vascular walls resulting in vessel narrowing, decreased blood flow, and increased risk of lesion rupture leading to myocardial infarction and stroke. The current study was undertaken to investigate whether inflammation in ATH can induce pyroptosis in vascular smooth muscle cells (SMC's). We therefore hypothesized that pyroptosis occurs and is inhibited by bone morphogenetic protein 7 (BMP7). We examined SMC pyroptosis at acute (D5) and midstage (D28) following disturbed flow-induced hemodynamic injury to the vascular wall using our partial left carotid artery ligation (PLCA) model. ApoE -/- mice (11±1 week old) were divided into three groups: Sham, PLCA, PLCA+BMP7 (200μg/kg; i.v) and arterial tissue was collected for immunohistochemical staining (IHC) and western blot (WB) analysis. At D5 and D28, IHC data demonstrated that PLCA significantly upregulated Toll-like receptor 4 (TLR4) and NLRP3 inflammasome components (NLRP3 and Caspase-1), indicating the initiation and activation of pyroptosis in SMC's (p < 0.05). Further, maturation of pro-IL-1β and pro-IL-18 released through cell membrane pores mediated by Caspase-11 were investigated. Our data shows a significant increase at D5 and D28 in IL-1β, IL-18, and Caspase-11 expression following PLCA, which was significantly improved upon treatment with BMP7 (p < 0.05). Western blot analysis supported these findings demonstrating initiation of pyroptosis via TLR4, upregulation of inflammasome components (Caspase-1 and NLRP3), and release of proinflammatory cytokines, IL-1β and IL-18 at D28, but not at D5. Overall, this study demonstrates that pyroptosis occurs in vascular smooth muscle cells in our PLCA model and that BMP7 administration attenuates pyroptosis significantly.
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Master of Science (M.S.)
College of Medicine
Length of Campus-only Access
Masters Thesis (Campus-only Access)
Garner, Kaley, "Bone Morphogenetic Protein 7 Inhibits Pyroptotic Cell Death in Vascular Smooth Muscle Cells of Atherosclerotic Apolipoprotein E -/- Mice" (2019). Electronic Theses and Dissertations. 6487.