This Article Full Text Full Text (PDF) All Versions of this Article: 25/1/174    most recent 01.ATV.0000148548.47755.22v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Liu, J. Articles by Sinensky, M. S. Search for Related Content PubMed PubMed Citation Articles by Liu, J. Articles by Sinensky, M. S. Related Collections Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors Apoptosis

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:174.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Reduced Macrophage Apoptosis Is Associated With Accelerated Atherosclerosis in Low-Density Lipoprotein Receptor-Null Mice

June Liu; Douglas P. Thewke; Yan Ru Su; MacRae F. Linton; Sergio Fazio; Michael S. Sinensky

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

This article has been cited by other articles:

				J. G. Dickhout, S. Basseri, and R. C. Austin Macrophage Function and Its Impact on Atherosclerotic Lesion Composition, Progression, and Stability: The Good, the Bad, and the Ugly Arterioscler. Thromb. Vasc. Biol., August 1, 2008; 28(8): 1413 - 1415. [Full Text] [PDF]

				H. Fujimoto, J.-i. Taguchi, Y. Imai, S. Ayabe, H. Hashimoto, H. Kobayashi, K. Ogasawara, T. Aizawa, M. Yamakado, R. Nagai, et al. Manganese superoxide dismutase polymorphism affects the oxidized low-density lipoprotein-induced apoptosis of macrophages and coronary artery disease Eur. Heart J., May 2, 2008; 29(10): 1267 - 1274. [Abstract] [Full Text] [PDF]

				A. B. Gerry and D. S. Leake A moderate reduction in extracellular pH protects macrophages against apoptosis induced by oxidized low density lipoprotein J. Lipid Res., April 1, 2008; 49(4): 782 - 789. [Abstract] [Full Text] [PDF]

				W.-S. Lim, J. M. Timmins, T. A. Seimon, A. Sadler, F. D. Kolodgie, R. Virmani, and I. Tabas Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo Circulation, February 19, 2008; 117(7): 940 - 951. [Abstract] [Full Text] [PDF]

				T. Ding, Z. Li, T. Hailemariam, S. Mukherjee, F. R. Maxfield, M.-P. Wu, and X.-C. Jiang SMS overexpression and knockdown: impact on cellular sphingomyelin and diacylglycerol metabolism, and cell apoptosis J. Lipid Res., February 1, 2008; 49(2): 376 - 385. [Abstract] [Full Text] [PDF]

				D. Namgaladze, A. Kollas, and B. Brune Oxidized LDL attenuates apoptosis in monocytic cells by activating ERK signaling J. Lipid Res., January 1, 2008; 49(1): 58 - 65. [Abstract] [Full Text] [PDF]

				C.-P. Liang, S. Han, T. Senokuchi, and A. R. Tall The Macrophage at the Crossroads of Insulin Resistance and Atherosclerosis Circ. Res., June 8, 2007; 100(11): 1546 - 1555. [Abstract] [Full Text] [PDF]

				H. Ait-Oufella, K. Kinugawa, J. Zoll, T. Simon, J. Boddaert, S. Heeneman, O. Blanc-Brude, V. Barateau, S. Potteaux, R. Merval, et al. Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice Circulation, April 24, 2007; 115(16): 2168 - 2177. [Abstract] [Full Text] [PDF]

				A. Wehinger, I. Tancevski, W. Schgoer, P. Eller, K. Hochegger, M. Morak, A. Hermetter, A. Ritsch, J. R. Patsch, and B. Foeger Phospholipid Transfer Protein Augments Apoptosis in THP-1-Derived Macrophages Induced by Lipolyzed Hypertriglyceridemic Plasma Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 908 - 915. [Abstract] [Full Text] [PDF]

				S. M. Schwartz, Z. S. Galis, M. E. Rosenfeld, and E. Falk Plaque Rupture in Humans and Mice Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 705 - 713. [Abstract] [Full Text] [PDF]

				J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]

				D. Namgaladze and B. Brune Phospholipase A2-Modified Low-Density Lipoprotein Activates the Phosphatidylinositol 3-Kinase-Akt Pathway and Increases Cell Survival in Monocytic Cells Arterioscler. Thromb. Vasc. Biol., November 1, 2006; 26(11): 2510 - 2516. [Abstract] [Full Text] [PDF]

				A. Baldan, L. Pei, R. Lee, P. Tarr, R. K. Tangirala, M. M. Weinstein, J. Frank, A. C. Li, P. Tontonoz, and P. A. Edwards Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr-/- and ApoE-/- Mice Transplanted With Abcg1-/- Bone Marrow Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2301 - 2307. [Abstract] [Full Text] [PDF]

				K. Fettucciari, I. Fetriconi, R. Mannucci, I. Nicoletti, A. Bartoli, S. Coaccioli, and P. Marconi Group B streptococcus induces macrophage apoptosis by calpain activation. J. Immunol., June 15, 2006; 176(12): 7542 - 7556. [Abstract] [Full Text] [PDF]

				A. Boullier, Y. Li, O. Quehenberger, W. Palinski, I. Tabas, J. L. Witztum, and Y. I. Miller Minimally Oxidized LDL Offsets the Apoptotic Effects of Extensively Oxidized LDL and Free Cholesterol in Macrophages Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1169 - 1176. [Abstract] [Full Text] [PDF]

				Y. Li, M.-C. Gerbod-Giannone, H. Seitz, D. Cui, E. Thorp, A. R. Tall, G. K. Matsushima, and I. Tabas Cholesterol-induced Apoptotic Macrophages Elicit an Inflammatory Response in Phagocytes, Which Is Partially Attenuated by the Mer Receptor J. Biol. Chem., March 10, 2006; 281(10): 6707 - 6717. [Abstract] [Full Text] [PDF]

				W.A. Boisvert, D.M. Rose, A. Boullier, O. Quehenberger, A. Sydlaske, K.A Johnson, L.K. Curtiss, and R. Terkeltaub Leukocyte Transglutaminase 2 Expression Limits Atherosclerotic Lesion Size Arterioscler. Thromb. Vasc. Biol., March 1, 2006; 26(3): 563 - 569. [Abstract] [Full Text] [PDF]

				I. Tabas Consequences and Therapeutic Implications of Macrophage Apoptosis in Atherosclerosis: The Importance of Lesion Stage and Phagocytic Efficiency Arterioscler. Thromb. Vasc. Biol., November 1, 2005; 25(11): 2255 - 2264. [Abstract] [Full Text] [PDF]

				N. E. Freeman, A. E. Rusinol, M. Linton, D. L. Hachey, S. Fazio, M. S. Sinensky, and D. Thewke Acyl-coenzyme A:cholesterol acyltransferase promotes oxidized LDL/oxysterol-induced apoptosis in macrophages J. Lipid Res., September 1, 2005; 46(9): 1933 - 1943. [Abstract] [Full Text] [PDF]

				K. J. Williams and I. Tabas Lipoprotein Retention--and Clues for Atheroma Regression Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1536 - 1540. [Abstract] [Full Text] [PDF]

				J. Zhou, S. Lhotak, B. A. Hilditch, and R. C. Austin Activation of the Unfolded Protein Response Occurs at All Stages of Atherosclerotic Lesion Development in Apolipoprotein E-Deficient Mice Circulation, April 12, 2005; 111(14): 1814 - 1821. [Abstract] [Full Text] [PDF]