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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03172015-102024 |
| Date | 18 March 2015 |
| Creators | Segedy, Amanda Kay |
| Contributors | Larry L. Swift, W. Gray Jerome, Colleen M. Brophy, MacRae F. Linton, Pampee P. Young |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03172015-102024/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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