N. A. Mansukhani1, Z. Wang1, V. P. Shively1, M. Kelly1, M. R. Kibbe2 1Northwestern University,Surgery,Chicago, IL, USA 2University Of North Carolina At Chapel Hill,Surgery,Chapel Hill, NC, USA
Introduction:
Atherosclerosis is the leading cause of death and disability in the United States. The manifestations of atherosclerotic occlusive disease affect men and women differently. Beyond estrogen, the etiologies for these differences are not well characterized. Stem cell antigen 1 (Sca-1) positive cells are multipotent progenitor cells that reside in the adventitia of arteries, just external to the external elastic lamina. Their role in atherosclerosis has not been defined. Thus, the purpose of this study was to characterize the expression of atherosclerosis over time in male and female low density lipoprotein receptor knockout (LDLR KO) mice, and to identify the role of Sca-1 progenitor cells in the development of atherosclerosis. We hypothesize that Sca-1 progenitor cells impact the development of atherosclerosis.
Methods:
Male and female LDLR KO, Sca-1 KO, and Sca-1/LDLR double KO mice were bred, genetically confirmed, and colonies maintained. To assess the development of atherosclerosis in male and female LDLR KO mice, mice were fed a high-fat diet for 8, 14, 18, and 22 weeks prior to sacrifice. To assess the role of Sca-1 progenitor cells in the development of atherosclerosis, male and female Sca-1/LDLR double KO mice were fed a high-fat diet for 14 weeks prior to sacrifice. Control mice consisted of LDLR KO and Sca-1/LDLR double KO mice fed regular chow. At the time of sacrifice, aortic roots were harvested and oil-red-O staining of the atherosclerotic area was quantified. n=4-6/treatment group.
Results:
Time-course analysis of the development of atherosclerosis in the aortic root of LDLR KO mice fed the high-fat diet for 8, 14, 18, and 22 weeks revealed 18.9%, 35.8%, 43.5%, and 47.4% atherosclerosis, respectively (P<0.001). Unexpectedly, female LDLR KO mice fed the high fat diet developed more severe atherosclerosis compared to males after 14 weeks (females 41.9% vs. males 32.3%), 18 weeks (females 48.3% vs. males 41.6%), and 22 weeks (females 48.8% vs. males 45.4%) (P<0.001). To determine the role of Sca-1 progenitor cells in this process, Sca-1/LDLR double KO mice fed the high-fat diet for 14 weeks were analyzed. Interestingly, female Sca-1/LDLR KO mice developed only 36.4% atherosclerosis, which was significantly less compared to the female LDLR KO mice (41.9%, p<0.05). Male Sca-1/LDLR KO mice developed 32.7% atherosclerosis, which was similar to male LDLR KO mice (32.3%, p=NS).
Conclusion:
Our results demonstrate that LDLR KO mice fed a high-fat diet develop progressive atherosclerosis in the aortic root over time and that female LDLR KO mice develop more atherosclerosis compared to male LDLR-KO mice. Additionally, Sca-1 progenitor cells appear to play an important role in the differential development of atherosclerosis between male and female mice and warrants further study.