Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice.

Liu J, Thewke DP, Su YR, Linton MF, Fazio S, Sinensky MS
Arterioscler Thromb Vasc Biol. 2005 25 (1): 174-9

PMID: 15499039 · PMCID: PMC2649706 · DOI:10.1161/01.ATV.0000148548.47755.22

OBJECTIVE - The majority of apoptotic cells in atherosclerotic lesions are macrophages. However, the pathogenic role of macrophage apoptosis in the development of atherosclerosis remains unclear. Elevated expression of Bax, one of the pivotal proapoptotic 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 examined the effect of Bax deficiency in bone marrow-derived leukocytes on the development of atherosclerosis in low-density lipoprotein receptor-null (LDLR-/-) mice.

METHODS AND RESULTS - Fourteen 8-week-old male LDLR-/- mice were lethally irradiated and reconstituted with either wild-type (WT) C57BL6 or Bax-null (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 aorta revealed a 49.2% increase (P=0.0259) in the mean lesion area of the Bax-/- group compared with the WT group. A 53% decrease in apoptotic macrophages in the Bax-/- group was found by TUNEL staining (P<0.05).

CONCLUSIONS - The reduction of apoptotic activity in macrophages stimulates atherosclerosis in LDLR-/- mice, which is consistent with the hypothesis that macrophage apoptosis suppresses the development of atherosclerosis.

MeSH Terms (20)

Animals Apoptosis Arteriosclerosis bcl-2-Associated X Protein Bone Marrow Cells Bone Marrow Transplantation Cholesterol Lipoproteins Lipoproteins, LDL Lymphocyte Count Lymphocytes Macrophages, Peritoneal Male Mice Mice, Inbred C57BL Mice, Inbred Strains Proto-Oncogene Proteins c-bcl-2 Receptors, LDL Staurosporine Triglycerides

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