Balint, Liz-Understanding the Role of Bim in Macrophage Apoptosis and Atherosclerosis (Dr. Bernardo Trigatti)

Understanding the Role of Bim in Macrophage Apoptosis and Atherosclerosis

Cardiovascular disease (CVD) is the leading cause of death worldwide. Atherosclerosis,  the underlying cause of CVD,  is an inflammatory disease characterized by sub-endothelial plaque formation within the arteries. Macrophages internalize accumulated lipoproteins in the sub-endothelium,  but excessive uptake induces endoplasmic reticulum stress and results in apoptosis. Dead macrophages are ineffectively removed and form a necrotic core that increases plaque instability and can result in plaque rupture,  causing myocardial infarction or stroke.   

Bim is a proapoptotic protein implicated in macrophage apoptosis. Cre/lox recombination was used to develop a macrophage-specific Bim knockout (Bim mKO) to investigate the impact of reduced apoptosis on atherogenesis. Male LDLR-/- mice received bone marrow transplants from LyzMCre/Cre (control) or LyzMCre/CreBimfl/fl (Bim mKO) mice and were fed a 10-week high fat diet. Following 10 weeks,  the heart,  aorta,  liver,  spleen,  and blood were collected. 

Histological analysis of the aortic sinus did not demonstrate significant differences in plaque or necrotic core sizes between treatment groups. Cleaved caspase 3 staining demonstrated that apoptosis in atherosclerotic plaques decreased,  but overall cell death,  shown by staining for DNA strand breaks,  did not change. This may suggest that these macrophages are dying through other pathways and may explain why there was no observed impact on atherogenesis. Interestingly,  Bim mKO significantly increased atheroprotective high density lipoprotein levels,  and may suggest that Bim plays an unexpected role in its homeostasis. Overall,  decreasing macrophage apoptosis through bone marrow Bim mKO does not appear to impact atherogenesis in LDLR-/- mice fed a 10-week high fat diet.