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Caveolin-1 regulates the anti-atherogenic properties of macrophages

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Abstract

Atherosclerosis is a complex disease initiated by the vascular accumulation of lipoproteins in the sub-endothelial space, followed by the infiltration of monocytes into the arterial intima. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and of various signaling pathways. In order to study specifically the role of macrophage Cav-1 in atherosclerosis, we used Cav-1 −/− Apoe −/− mice and transplanted them with bone marrow (BM) cells obtained from Cav-1 +/+ Apoe −/− or Cav-1 −/− Apoe −/− mice and vice versa. We found that Cav-1 +/+ mice harboring Cav-1 −/− BM-derived macrophages developed significantly larger lesions than Cav-1 +/+ mice harboring Cav-1 +/+ BM-derived macrophages. Cav-1 −/− macrophages were more susceptible to apoptosis and more prone to induce inflammation. The present study provides clear evidence that the absence of Cav-1 in macrophage is pro-atherogenic, whereas its absence in endothelial cells protects against atherosclerotic lesion formation. These findings demonstrate the cell-specific role of Cav-1 during the development of this disease.

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References

  • Anwar A, Zahid AA, Scheidegger KJ, Brink M, Delafontaine P (2002) Tumor necrosis factor-alpha regulates insulin-like growth factor-1 and insulin-like growth factor binding protein-3 expression in vascular smooth muscle. Circulation 105:1220–1225

    Article  CAS  PubMed  Google Scholar 

  • Bian F, Yang X, Zhou F, Wu PH, Xing S, Xu G, Li W, Chi J, Ouyang C, Zhang Y, Xiong B, Li Y, Zheng T, Wu D, Chen X, Jin S (2014) C-reactive protein promotes atherosclerosis by increasing LDL transcytosis across endothelial cells. Br J Pharmacol 171:2671–2684

    Article  CAS  PubMed  Google Scholar 

  • Boisvert WA, Spangenberg J, Curtiss LK (1995) Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation. J Clin Invest 96:1118–1124

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bosch M, Mari M, Gross SP, Fernandez-Checa JC, Pol A (2011a) Mitochondrial cholesterol: a connection between caveolin, metabolism, and disease. Traffic 12:1483-1489

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bosch M, Mari M, Herms A, Fernandez A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, Gonzalez-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, Garcia-Ruiz C, Perez-Navarro E, Fernandez-Checa JC, Pol A (2011b) Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility. Curr Biol 21:681–686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cameron PL, Ruffin JW, Bollag R, Rasmussen H, Cameron RS (1997) Identification of caveolin and caveolin-related proteins in the brain. J Neurosci 17:9520–9535

    CAS  PubMed  Google Scholar 

  • Dansky HM, Barlow CB, Lominska C, Sikes JL, Kao C, Weinsaft J, Cybulsky MI, Smith JD (2001) Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb Vasc Biol 21:1662–1667

    Article  CAS  PubMed  Google Scholar 

  • Dong Y, Zhang M, Liang B, Xie Z, Zhao Z, Asfa S, Choi HC, Zou MH (2010) Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation 121:792–803

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452

    Article  CAS  PubMed  Google Scholar 

  • Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow ME, Fazio S, Wiest MM, Watkins SM, Linton MF, Hotamisligil GS (2009) Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis. Nat Med 15:1383–1391

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Feng B, Yao PM, Li Y, Devlin CM, Zhang D, Harding HP, Sweeney M, Rong JX, Kuriakose G, Fisher EA, Marks AR, Ron D, Tabas I (2003) The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat Cell Biol 5:781–792

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Hernando C, Yu J, Suarez Y, Rahner C, Davalos A, Lasuncion MA, Sessa WC (2009) Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis. Cell Metab 10:48–54

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Fernandez-Hernando C, Yu J, Davalos A, Prendergast J, Sessa WC (2010) Endothelial-specific overexpression of caveolin-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 177:998–1003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Feron O, Dessy C, Desager JP, Balligand JL (2001) Hydroxy-methylglutaryl-coenzyme A reductase inhibition promotes endothelial nitric oxide synthase activation through a decrease in caveolin abundance. Circulation 103:113–118

    Article  CAS  PubMed  Google Scholar 

  • Fra AM, Williamson E, Simons K, Parton RG (1994) Detergent-insoluble glycolipid microdomains in lymphocytes in the absence of caveolae. J Biol Chem 269:30745–30748

    CAS  PubMed  Google Scholar 

  • Frank PG (2010) Endothelial caveolae and caveolin-1 as key regulators of atherosclerosis. Am J Pathol 177:544–546

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Frank PG, Lisanti MP (2004) Caveolin-1 and caveolae in atherosclerosis: differential roles in fatty streak formation and neointimal hyperplasia. Curr Opin Lipidol 15:523–529

    Article  CAS  PubMed  Google Scholar 

  • Frank PG, Lee H, Park DS, Tandon NN, Scherer PE, Lisanti MP (2004) Genetic ablation of caveolin-1 confers protection against atherosclerosis. Arterioscler Thromb Vasc Biol 24:98–105

    Article  CAS  PubMed  Google Scholar 

  • Frank PG, Cheung MW, Pavlides S, Llaverias G, Park DS, Lisanti MP (2006) Caveolin-1 and regulation of cellular cholesterol homeostasis. Am J Physiol Heart Circ Physiol 291:H677–H686

    Article  CAS  PubMed  Google Scholar 

  • Frank PG, Pavlides S, Cheung MW, Daumer K, Lisanti MP (2008) Role of caveolin-1 in the regulation of lipoprotein metabolism. Am J Physiol Cell Physiol 295:C242–C248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Gargalovic PS, Imura M, Zhang B, Gharavi NM, Clark MJ, Pagnon J, Yang WP, He A, Truong A, Patel S, Nelson SF, Horvath S, Berliner JA, Kirchgessner TG, Lusis AJ (2006) Identification of inflammatory gene modules based on variations of human endothelial cell responses to oxidized lipids. Proc Natl Acad Sci U S A 103:12741–12746

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516

    Article  CAS  PubMed  Google Scholar 

  • Gregor MG, Hotamisligil GS (2007) Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48:1905-1914

    Article  CAS  PubMed  Google Scholar 

  • Hassan GS, Jasmin JF, Schubert W, Frank PG, Lisanti MP (2004) Caveolin-1 deficiency stimulates neointima formation during vascular injury. Biochemistry 43:8312–8321

    Article  CAS  PubMed  Google Scholar 

  • Kockx MM, Herman AG (2000) Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res 45:736–746

    Article  CAS  PubMed  Google Scholar 

  • Kockx MM, De Meyer GR, Muhring J, Jacob W, Bult H, Herman AG (1998) Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation 97:2307–2315

    Article  CAS  PubMed  Google Scholar 

  • Li J, Scherl A, Medina F, Frank PG, Kitsis RN, Tanowitz HB, Sotgia F, Lisanti MP (2005) Impaired phagocytosis in caveolin-1 deficient macrophages. Cell Cycle 4:1596–1605

    Google Scholar 

  • Libby P, Okamoto Y, Rocha VZ, Folco E (2010) Inflammation in atherosclerosis: transition from theory to practice. Circ J 74:213–220

    Article  CAS  PubMed  Google Scholar 

  • Linton MF, Atkinson JB, Fazio S (1995) Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science 267:1034–1037

    Article  CAS  PubMed  Google Scholar 

  • Lusis AJ (2000) Atherosclerosis. Nature 407:233–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Myoishi M, Hao H, Minamino T, Watanabe K, Nishihira K, Hatakeyama K, Asada Y, Okada K, Ishibashi-Ueda H, Gabbiani G, Bochaton-Piallat ML, Mochizuki N, Kitakaze M (2007) Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation 116:1226–1233

    Article  PubMed  Google Scholar 

  • Nakashima Y, Raines EW, Plump AS, Breslow JL, Ross R (1998) Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 18:842–851

    Article  CAS  PubMed  Google Scholar 

  • Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389

    Article  CAS  PubMed  Google Scholar 

  • Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137–1140

    Article  PubMed  Google Scholar 

  • Palade GE (1953) Fine structure of blood capillaries. J Appl Phys 24:1424

    Google Scholar 

  • Pavlides S, Gutierrez-Pajares JL, Iturrieta J, Lisanti MP, Frank PG (2014) Endothelial caveolin-1 plays a major role in the development of atherosclerosis. Cell Tissue Res 356:147–157

    Article  CAS  PubMed  Google Scholar 

  • Petremand J, Puyal J, Chatton JY, Duprez J, Allagnat F, Frias M, James RW, Waeber G, Jonas JC, Widmann C (2012) HDLs protect pancreatic beta-cells against ER stress by restoring protein folding and trafficking. Diabetes 61:1100–1111

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Plenz GA, Hofnagel O, Robenek H (2004) Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation 109:e7–e8

    Article  CAS  PubMed  Google Scholar 

  • Puyal J, Petremand J, Dubuis G, Rummel C, Widmann C (2013) HDLs protect the MIN6 insulinoma cell line against tunicamycin-induced apoptosis without inhibiting ER stress and without restoring ER functionality. Mol Cell Endocrinol 381:291–301

    Article  CAS  PubMed  Google Scholar 

  • Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE, Lisanti MP (2001a) Caveolin-1 deficient mice are lean, resistant to diet-induced obesity, and show hyper-triglyceridemia with adipocyte abnormalities. J Biol Chem 277:8635–8647

    Article  PubMed  Google Scholar 

  • Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, Macaluso F, Russell RG, Li M, Pestell RG, Di Vizio D, Hou H Jr, Kneitz B, Lagaud G, Christ GJ, Edelmann W, Lisanti MP (2001b) Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 276:38121–38138

    Article  CAS  PubMed  Google Scholar 

  • Rocha VZ, Folco EJ, Sukhova G, Shimizu K, Gotsman I, Vernon AH, Libby P (2008) Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 103:467–476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Scherer PE, Lewis RY, Volonte D, Engelman JA, Galbiati F, Couet J, Kohtz DS, van Donselaar E, Peters P, Lisanti MP (1997) Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo. J Biol Chem 272:29337–29346

    Article  CAS  PubMed  Google Scholar 

  • Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480

    Article  CAS  PubMed  Google Scholar 

  • Schwenke DC, Carew TE (1989) Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis 9:908–918

    Article  CAS  PubMed  Google Scholar 

  • Tabas I (2005) Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 25:2255–2264

    Article  CAS  PubMed  Google Scholar 

  • Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13:184–190

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Thorp E, Li G, Seimon TA, Kuriakose G, Ron D, Tabas I (2009) Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe−/− and Ldlr−/− mice lacking CHOP. Cell Metab 9:474–481

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tsukano H, Gotoh T, Endo M, Miyata K, Tazume H, Kadomatsu T, Yano M, Iwawaki T, Kohno K, Araki K, Mizuta H, Oike Y (2010) The endoplasmic reticulum stress-C/EBP homologous protein pathway-mediated apoptosis in macrophages contributes to the instability of atherosclerotic plaques. Arterioscler Thromb Vasc Biol 30:1925–1932

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Yang X, Bian F, Wu P, Xing S, Xu G, Li W, Chi J, Ouyang C, Zheng T, Wu D, Zhang Y, Li Y, Jin S (2014) TNF-alpha promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: crosstalk between NF-kappaB and PPAR-gamma. J Mol Cell Cardiol 72:85–94

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Lhotak S, Hilditch BA, Austin RC (2005) Activation of the unfolded protein response occurs at all stages of atherosclerotic lesion development in apolipoprotein E-deficient mice. Circulation 111:1814–1821

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank Dr. Iset Medina Vera for her technical support. P.G.F. was supported by grants from the Jane Barsumian/Mary Lyons Trust and the W.W. Smith Trust Fund. M.P.L. was supported by grants from the National Institutes of Health and the American Heart Association.

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Authors and Affiliations

  1. Manchester Breast Centre & Breakthrough Breast Cancer Research Unit, Paterson Institute for Cancer Research, School of Cancer, Enabling Sciences and Technology, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

    Stephanos Pavlides & Michael P. Lisanti

  2. Department of Stem Cell Biology & Regenerative Medicine, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Jorge L. Gutierrez-Pajares, Christos Pavlides & Philippe G. Frank

  3. Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    Jorge L. Gutierrez-Pajares, Sanjay Katiyar & Richard G. Pestell

  4. Department of Pharmaceutical Sciences Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, PA, USA

    Jean-François Jasmin & Isabelle Mercier

  5. Department of Pathology, Thomas Jefferson University, Philadelphia, PA, USA

    Rhonda Walters

  6. Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA

    Philippe G. Frank

  7. INSERM UMR1069 “Nutrition, Croissance et Cancer”, Faculté de Médecine, Université François Rabelais de Tours, 37032, Tours Cedex, France

    Philippe G. Frank

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  1. Stephanos Pavlides
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  2. Jorge L. Gutierrez-Pajares
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  10. Philippe G. Frank
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Correspondence to Philippe G. Frank.

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Pavlides, S., Gutierrez-Pajares, J.L., Katiyar, S. et al. Caveolin-1 regulates the anti-atherogenic properties of macrophages. Cell Tissue Res 358, 821–831 (2014). https://doi.org/10.1007/s00441-014-2008-4

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  • DOI: https://doi.org/10.1007/s00441-014-2008-4

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