Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

12-2004

Committee Chair or Co-Chairs

Douglas P. Thewke

Committee Members

Michael S. Sinensky, John J. Laffan, Balvin H.L. Chua, Antonio E. Rusinol

Abstract

The presence of apoptotic cells in atherosclerotic lesions has been broadly reported in the past ten years. The majority of these apoptotic cells are macrophages. However, the pathogenic role of macrophage apoptosis in the development of atherosclerosis remains to be elucidated. Elevated expression of Bax, one of the pivotal pro-apoptotic proteins of the Bcl-2 family, has been found in human atherosclerotic plaques. Activation of Bax also occurs in free cholesterol-loaded and oxysterol treated mouse macrophages. In this study, we evaluated the influence of Bax deficiency on apoptosis in macrophage-like P388D1 cells by using small interfering RNA (siRNA) to suppress Bax expression, as well as in peritoneal macrophages isolated from Bax null mice (Bax-/-). Apoptotic activities in both cell types deficient for Bax were significantly reduced compared to that in control cells. To examine the effect of macrophage Bax deficiency on the development of atherosclerosis, fourteen 8-week-old male LDL-receptor null (LDLR-/-) mice were lethally irradiated and reconstituted with either wild type (WT) C57BL6 or Bax-/- bone marrow. Three weeks later, the mice were challenged with a Western diet for 10 weeks. No differences were found in the plasma cholesterol level between the WT and Bax-/- group. However, quantitation of cross sections from proximal aortas revealed a 49.2% increase (P=0.0259) in the mean lesion area of the Bax-/- group compared to the WT group. A 53% decrease in apoptotic macrophages in the Bax-/- group was found by TUNEL staining (P<0.05). In conclusion, Bax deficiency produces a reduction of apoptotic activity in macrophages and is associated with the accelerated atherosclerosis in LDLR null mice fed a Western diet. These results strongly support our hypothesis that macrophage apoptosis suppresses the development of atherosclerosis.

Document Type

Dissertation - Open Access

Copyright

Copyright by the authors.

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