Cell and Tissue Research

, Volume 358, Issue 3, pp 821–831 | Cite as

Caveolin-1 regulates the anti-atherogenic properties of macrophages

  • Stephanos Pavlides
  • Jorge L. Gutierrez-Pajares
  • Sanjay Katiyar
  • Jean-François Jasmin
  • Isabelle Mercier
  • Rhonda Walters
  • Christos Pavlides
  • Richard G. Pestell
  • Michael P. Lisanti
  • Philippe G. Frank
Regular Article


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.


Caveolin Caveolae Macrophage Atherosclerosis Lipoproteins Mouse 



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.


  1. 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 105:1220–1225PubMedCrossRefGoogle Scholar
  2. 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 171:2671–2684PubMedCrossRefGoogle Scholar
  3. Boisvert WA, Spangenberg J, Curtiss LK (1995) Treatment of severe hypercholesterolemia in apolipoprotein E-deficient mice by bone marrow transplantation. J Clin Invest 96:1118–1124PubMedCentralPubMedCrossRefGoogle Scholar
  4. Bosch M, Mari M, Gross SP, Fernandez-Checa JC, Pol A (2011a) Mitochondrial cholesterol: a connection between caveolin, metabolism, and disease. Traffic 12:1483-1489PubMedCentralPubMedCrossRefGoogle Scholar
  5. 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 21:681–686PubMedCentralPubMedCrossRefGoogle Scholar
  6. Cameron PL, Ruffin JW, Bollag R, Rasmussen H, Cameron RS (1997) Identification of caveolin and caveolin-related proteins in the brain. J Neurosci 17:9520–9535PubMedGoogle Scholar
  7. 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 21:1662–1667PubMedCrossRefGoogle Scholar
  8. 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 121:792–803PubMedCentralPubMedCrossRefGoogle Scholar
  9. 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 293:2449–2452PubMedCrossRefGoogle Scholar
  10. 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 15:1383–1391PubMedCentralPubMedCrossRefGoogle Scholar
  11. 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 5:781–792PubMedCrossRefGoogle Scholar
  12. 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 10:48–54PubMedCentralPubMedCrossRefGoogle Scholar
  13. 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 177:998–1003PubMedCentralPubMedCrossRefGoogle Scholar
  14. 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 103:113–118PubMedCrossRefGoogle Scholar
  15. Fra AM, Williamson E, Simons K, Parton RG (1994) Detergent-insoluble glycolipid microdomains in lymphocytes in the absence of caveolae. J Biol Chem 269:30745–30748PubMedGoogle Scholar
  16. Frank PG (2010) Endothelial caveolae and caveolin-1 as key regulators of atherosclerosis. Am J Pathol 177:544–546PubMedCentralPubMedCrossRefGoogle Scholar
  17. Frank PG, Lisanti MP (2004) Caveolin-1 and caveolae in atherosclerosis: differential roles in fatty streak formation and neointimal hyperplasia. Curr Opin Lipidol 15:523–529PubMedCrossRefGoogle Scholar
  18. 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 24:98–105PubMedCrossRefGoogle Scholar
  19. 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–H686PubMedCrossRefGoogle Scholar
  20. 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–C248PubMedCentralPubMedCrossRefGoogle Scholar
  21. 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 103:12741–12746PubMedCentralPubMedCrossRefGoogle Scholar
  22. Glass CK, Witztum JL (2001) Atherosclerosis. The road ahead. Cell 104:503–516PubMedCrossRefGoogle Scholar
  23. Gregor MG, Hotamisligil GS (2007) Adipocyte stress: the endoplasmic reticulum and metabolic disease. J Lipid Res 48:1905-1914PubMedCrossRefGoogle Scholar
  24. Hassan GS, Jasmin JF, Schubert W, Frank PG, Lisanti MP (2004) Caveolin-1 deficiency stimulates neointima formation during vascular injury. Biochemistry 43:8312–8321PubMedCrossRefGoogle Scholar
  25. Kockx MM, Herman AG (2000) Apoptosis in atherosclerosis: beneficial or detrimental? Cardiovasc Res 45:736–746PubMedCrossRefGoogle Scholar
  26. 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 97:2307–2315PubMedCrossRefGoogle Scholar
  27. 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 4:1596–1605Google Scholar
  28. Libby P, Okamoto Y, Rocha VZ, Folco E (2010) Inflammation in atherosclerosis: transition from theory to practice. Circ J 74:213–220PubMedCrossRefGoogle Scholar
  29. Linton MF, Atkinson JB, Fazio S (1995) Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science 267:1034–1037PubMedCrossRefGoogle Scholar
  30. Lusis AJ (2000) Atherosclerosis. Nature 407:233–241PubMedCentralPubMedCrossRefGoogle Scholar
  31. 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 116:1226–1233PubMedCrossRefGoogle Scholar
  32. 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 18:842–851PubMedCrossRefGoogle Scholar
  33. Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389PubMedCrossRefGoogle Scholar
  34. 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 313:1137–1140PubMedCrossRefGoogle Scholar
  35. Palade GE (1953) Fine structure of blood capillaries. J Appl Phys 24:1424Google Scholar
  36. 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 356:147–157PubMedCrossRefGoogle Scholar
  37. 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 61:1100–1111PubMedCentralPubMedCrossRefGoogle Scholar
  38. Plenz GA, Hofnagel O, Robenek H (2004) Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation 109:e7–e8PubMedCrossRefGoogle Scholar
  39. 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 381:291–301PubMedCrossRefGoogle Scholar
  40. 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 277:8635–8647PubMedCrossRefGoogle Scholar
  41. 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 276:38121–38138PubMedCrossRefGoogle Scholar
  42. 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 103:467–476PubMedCentralPubMedCrossRefGoogle Scholar
  43. 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 272:29337–29346PubMedCrossRefGoogle Scholar
  44. Schrijvers DM, De Meyer GR, Herman AG, Martinet W (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480PubMedCrossRefGoogle Scholar
  45. 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 9:908–918PubMedCrossRefGoogle Scholar
  46. Tabas I (2005) Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 25:2255–2264PubMedCrossRefGoogle Scholar
  47. Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13:184–190PubMedCentralPubMedCrossRefGoogle Scholar
  48. 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 9:474–481PubMedCentralPubMedCrossRefGoogle Scholar
  49. 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 30:1925–1932PubMedCrossRefGoogle Scholar
  50. 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 72:85–94PubMedCrossRefGoogle Scholar
  51. 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 111:1814–1821PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Stephanos Pavlides
    • 1
  • Jorge L. Gutierrez-Pajares
    • 2
    • 3
  • Sanjay Katiyar
    • 3
  • Jean-François Jasmin
    • 4
  • Isabelle Mercier
    • 4
  • Rhonda Walters
    • 5
  • Christos Pavlides
    • 2
  • Richard G. Pestell
    • 3
  • Michael P. Lisanti
    • 1
  • Philippe G. Frank
    • 2
    • 6
    • 7
  1. 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 CentreUniversity of ManchesterManchesterUK
  2. 2.Department of Stem Cell Biology & Regenerative Medicine, Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA
  3. 3.Department of Cancer Biology, Kimmel Cancer CenterThomas Jefferson UniversityPhiladelphiaUSA
  4. 4.Department of Pharmaceutical Sciences Philadelphia College of PharmacyUniversity of the SciencesPhiladelphiaUSA
  5. 5.Department of PathologyThomas Jefferson UniversityPhiladelphiaUSA
  6. 6.Department of Biochemistry and Molecular BiologyThomas Jefferson UniversityPhiladelphiaUSA
  7. 7.INSERM UMR1069 “Nutrition, Croissance et Cancer”, Faculté de MédecineUniversité François Rabelais de ToursTours CedexFrance

Personalised recommendations