Published online before print October 21, 2004, doi: 10.1161/01.ATV.0000148548.47755.22
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© 2005 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Reduced Macrophage Apoptosis Is Associated With Accelerated Atherosclerosis in Low-Density Lipoprotein Receptor-Null Mice
From the Department of Biochemistry and Molecular Biology (J.L., D.P.T., M.S.S.), East Tennessee State University, Johnson City; and the Departments of Medicine (Y.R.S., M.F.L., S.F.), Pharmacology (M.F.L.), and Pathology (S.F.), Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Michael S. Sinensky, PhD, East Tennessee State University, PO Box 70581, Johnson City, TN 37614 (E-mail sinensky{at}mail.etsu.edu) or Sergio Fazio, MD, PhD, Vanderbilt University Medical School, 2220 Pierce Ave., PRB 315, Nashville, TN 37232 (E-mail sergio.fazio{at}Vanderbilt.edu)
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.
Bone marrow transplantation was performed to study the pathogenic role of macrophage apoptosis in atherogenesis. We found the atherosclerotic lesions in the aortic roots of low-density lipoprotein receptor-null mice reconstituted with Bax–/– bone marrow were increased by 49.2% compared with those in wild-type group, indicating macrophage apoptosis suppresses the development of atherosclerosis.
Key Words: apoptosis • atherosclerosis • macrophage • Bax • smooth muscle cell
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