HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 35, 37030-37039, August 27, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/35/37030    most recent M405195200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Li, Y. Articles by Tabas, I. Search for Related Content PubMed PubMed Citation Articles by Li, Y. Articles by Tabas, I. Social Bookmarking                      What's this?

Enrichment of Endoplasmic Reticulum with Cholesterol Inhibits Sarcoplasmic-Endoplasmic Reticulum Calcium ATPase-2b Activity in Parallel with Increased Order of Membrane Lipids

IMPLICATIONS FOR DEPLETION OF ENDOPLASMIC RETICULUM CALCIUM STORES AND APOPTOSIS IN CHOLESTEROL-LOADED MACROPHAGES^*

Yankun Li, Mingtao Ge, Laura Ciani¶, George Kuriakose, Emily J. Westover||, Miroslav Dura**, Douglas F. Covey||, Jack H. Freed, Frederick R. Maxfield, Jonathan Lytton¶¶, and Ira Tabas||||

From the Departments of Medicine, Anatomy & Cell Biology, and Physiology and Cellular Biophysics and the ^**Center for Molecular Cardiology, Columbia University, New York, New York 10032, the Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853, the ^||Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, the Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, and the Department of Biochemistry and Molecular Biology, University of Calgary Health Sciences Center, Calgary, Alberta T2N 4N1, Canada

Macrophages in advanced atherosclerotic lesions accumulate large amounts of unesterified, or "free," cholesterol (FC). FC accumulation induces macrophage apoptosis, which likely contributes to plaque destabilization. Apoptosis is triggered by the enrichment of the endoplasmic reticulum (ER) with FC, resulting in depletion of ER calcium stores, and induction of the unfolded protein response. To explain the mechanism of ER calcium depletion, we hypothesized that FC enrichment of the normally cholesterol-poor ER membrane inhibits the macrophage ER calcium pump, sarcoplasmic-endoplasmic reticulum calcium ATPase-2b (SERCA2b). FC enrichment of ER membranes to a level similar to that occuring in vivo inhibited both the ATPase activity and calcium sequestration function of SERCA2b. Enrichment of ER with ent-cholesterol or 14:0-18:0 phosphatidylcholine, which possess the membrane-ordering properties of cholesterol, also inhibited SERCA2b. Moreover, at various levels of FC enrichment of ER membranes, there was a very close correlation between increasing membrane lipid order, as monitored by 16-doxyl-phosphatidycholine electron spin resonance, and SERCA2b inhibition. In view of these data, we speculate that SERCA2b, a conformationally active protein with 11 membrane-spanning regions, loses function due to decreased conformational freedom in FC-ordered membranes. This biophysical model may underlie the critical connection between excess cholesterol, unfolded protein response induction, macrophage death, and plaque destabilization in advanced atherosclerosis.

Received for publication, May 10, 2004 , and in revised form, June 21, 2004.

^* This work was supported in part by National Institutes of Health Grants HL75662 and HL54591 (to I. T.), HL57560 (to I. T. and F. R. M.), RR016292 and GM25862 (to J. H. F.), Cardiovascular Research Training Grant 55935 (to E. J. W.), National Institutes of Health Grant GM47969 (to D. F. C.), research support from the Heart & Stroke Foundation of Alberta, NWT, and Nunavut (to J. L.), and the University of Florence and the Italian Consorzio Sistemi a Grande Interfase (to L. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Current address: Dept. of Chemistry, University of Florence, Firenze, Italy.

^¶¶ Senior Scholar of the Alberta Heritage Foundation for Medical Research and an Investigator of the Canadian Institutes of Health Research.

^|||| To whom correspondence and reprint requests should be addressed: Dept. of Medicine, Columbia University, 630 West 168th St., New York, NY 10032. Tel.: 212-305-9430; Fax: 212-305-4834; E-mail: iat1{at}columbia.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Li, Y. Zhang, B. Dorweiler, D. Cui, T. Wang, C. W. Woo, C. S. Brunkan, C. Wolberger, S.-i. Imai, and I. Tabas Extracellular Nampt Promotes Macrophage Survival via a Nonenzymatic Interleukin-6/STAT3 Signaling Mechanism J. Biol. Chem., December 12, 2008; 283(50): 34833 - 34843. [Abstract] [Full Text] [PDF]

				M. T. Flowers, M. P. Keller, Y. Choi, H. Lan, C. Kendziorski, J. M. Ntambi, and A. D. Attie Liver gene expression analysis reveals endoplasmic reticulum stress and metabolic dysfunction in SCD1-deficient mice fed a very low-fat diet Physiol Genomics, May 1, 2008; 33(3): 361 - 372. [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]

				C. C. Glembotski Endoplasmic Reticulum Stress in the Heart Circ. Res., November 9, 2007; 101(10): 975 - 984. [Abstract] [Full Text] [PDF]

				S. Bao, Y. Li, X. Lei, M. Wohltmann, W. Jin, A. Bohrer, C. F. Semenkovich, S. Ramanadham, I. Tabas, and J. Turk Attenuated Free Cholesterol Loading-induced Apoptosis but Preserved Phospholipid Composition of Peritoneal Macrophages from Mice That Do Not Express Group VIA Phospholipase A2 J. Biol. Chem., September 14, 2007; 282(37): 27100 - 27114. [Abstract] [Full Text] [PDF]

				M. Gamerdinger, A. B. Clement, and C. Behl Cholesterol-Like Effects of Selective Cyclooxygenase Inhibitors and Fibrates on Cellular Membranes and Amyloid-beta Production Mol. Pharmacol., July 1, 2007; 72(1): 141 - 151. [Abstract] [Full Text] [PDF]

				G. H. Tansley, B. L. Burgess, M. T. Bryan, Y. Su, V. Hirsch-Reinshagen, J. Pearce, J. Y. Chan, A. Wilkinson, J. Evans, K. E. Naus, et al. The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of {beta}-amyloid precursor protein J. Lipid Res., May 1, 2007; 48(5): 1022 - 1034. [Abstract] [Full Text] [PDF]

				Y. Li and I. Tabas The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis J. Leukoc. Biol., February 1, 2007; 81(2): 483 - 491. [Abstract] [Full Text] [PDF]

				T. A. Seimon, A. Obstfeld, K. J. Moore, D. T. Golenbock, and I. Tabas Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages PNAS, December 26, 2006; 103(52): 19794 - 19799. [Abstract] [Full Text] [PDF]

				N. M. Borradaile, X. Han, J. D. Harp, S. E. Gale, D. S. Ory, and J. E. Schaffer Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death J. Lipid Res., December 1, 2006; 47(12): 2726 - 2737. [Abstract] [Full Text] [PDF]

				L. Bao, Y. Li, S.-X. Deng, D. Landry, and I. Tabas Sitosterol-containing Lipoproteins Trigger Free Sterol-induced Caspase-independent Death in ACAT-competent Macrophages J. Biol. Chem., November 3, 2006; 281(44): 33635 - 33649. [Abstract] [Full Text] [PDF]

				B. Zhao, Y. Li, C. Buono, S. W. Waldo, N. L. Jones, M. Mori, and H. S. Kruth Constitutive Receptor-independent Low Density Lipoprotein Uptake and Cholesterol Accumulation by Macrophages Differentiated from Human Monocytes with Macrophage-Colony-stimulating Factor (M-CSF) J. Biol. Chem., June 9, 2006; 281(23): 15757 - 15762. [Abstract] [Full Text] [PDF]

				D. Rodriguez-Agudo, S. Ren, P. B. Hylemon, R. Montanez, K. Redford, R. Natarajan, M. A. Medina, G. Gil, and W. M. Pandak Localization of StarD5 cholesterol binding protein J. Lipid Res., June 1, 2006; 47(6): 1168 - 1175. [Abstract] [Full Text] [PDF]

				N. Wang, M. Ranalletta, F. Matsuura, F. Peng, and A. R. Tall LXR-Induced Redistribution of ABCG1 to Plasma Membrane in Macrophages Enhances Cholesterol Mass Efflux to HDL Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1310 - 1316. [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]

				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]

				T. DeVries-Seimon, Y. Li, P. M. Yao, E. Stone, Y. Wang, R. J. Davis, R. Flavell, and I. Tabas Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor J. Cell Biol., October 10, 2005; 171(1): 61 - 73. [Abstract] [Full Text] [PDF]

				E. E. Griffin, J. C. Ullery, B. E. Cox, and W. G. Jerome Aggregated LDL and lipid dispersions induce lysosomal cholesteryl ester accumulation in macrophage foam cells J. Lipid Res., October 1, 2005; 46(10): 2052 - 2060. [Abstract] [Full Text] [PDF]

				H. Zhou, W. M. Pandak Jr., V. Lyall, R. Natarajan, and P. B. Hylemon HIV Protease Inhibitors Activate the Unfolded Protein Response in Macrophages: Implication for Atherosclerosis and Cardiovascular Disease Mol. Pharmacol., September 1, 2005; 68(3): 690 - 700. [Abstract] [Full Text] [PDF]

				K. Yaraei, L. A. Campbell, X. Zhu, W. C. Liles, C.-c. Kuo, and M. E. Rosenfeld Chlamydia pneumoniae Augments the Oxidized Low-Density Lipoprotein-Induced Death of Mouse Macrophages by a Caspase-Independent Pathway Infect. Immun., July 1, 2005; 73(7): 4315 - 4322. [Abstract] [Full Text] [PDF]

				Y. Li, R. F. Schwabe, T. DeVries-Seimon, P. M. Yao, M.-C. Gerbod-Giannone, A. R. Tall, R. J. Davis, R. Flavell, D. A. Brenner, and I. Tabas Free Cholesterol-loaded Macrophages Are an Abundant Source of Tumor Necrosis Factor-{alpha} and Interleukin-6: MODEL OF NF-{kappa}B- AND MAP KINASE-DEPENDENT INFLAMMATION IN ADVANCED ATHEROSCLEROSIS J. Biol. Chem., June 10, 2005; 280(23): 21763 - 21772. [Abstract] [Full Text] [PDF]