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Title page for ETD etd-03172015-102024


Type of Document Dissertation
Author Segedy, Amanda Kay
URN etd-03172015-102024
Title Novel Atheroprotective Mediators: SPRR3-expressing Vascular Smooth Muscle Cells
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Larry L. Swift Committee Chair
Colleen M. Brophy Committee Member
MacRae F. Linton Committee Member
Pampee P. Young Committee Member
W. Gray Jerome Committee Member
Keywords
  • plaque rupture
  • VSMCs
  • atherosclerosis
Date of Defense 2015-02-27
Availability unrestricted
Abstract
Atherosclerosis is the driving force behind cardiovascular disease, the principal cause of death in the world today. To complement currently available interventions, such as statins which reduce risk of a major cardiac event by only approximately 30%, a search for atheroprotective genes was initiated. Our study uncovered SPRR3 as the first identified atheroprotective protein expressed specifically in atheroma VSMCs. Loss of SPRR3 led to increased atherosclerosis progression independently of bone-marrow-derived cell SPRR3 expression. However, the observed increase in atherosclerosis was associated with a reduction in maintenance of atheroma VSMC content. This reduced VSMC content occurred, at least in part, due to an Akt-dependent reduction in VSMC survival in SPRR3-deficient atheroprone animals. Loss of SPRR3 expression also contributed to features of atheroma instability, including increased lipid-rich core size, reduced fibrous cap collagen content, and reduced fibrous cap thickness in brachiocephalic artery atheromas. In coronary arteries, SPRR3 loss contributed to a significant increase in the burden of complex atheromas as compared to fatty streaks and intermediate stage atheromas. In vitro, we observed a reduction in VSMC collagen type I mRNA and protein synthesis in SPRR3-deficient VSMCs. Our data indicate that SPRR3 promotes an atheroprotective response in atheroma VSMCs by enhancing VSMC survival and increasing collagen type I synthesis. The atheroma-specific expression pattern of SPRR3, moreover, uniquely positions this protein as a potential source of interventions for delaying progression and promoting stability of atheromas.
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