FUNCTIONAL HIERARCHY OF REMNANT LIPOPROTEIN RECEPTORS

Summary

Principal Investigator: S Fazio
Affiliation: Vanderbilt University
Country: USA
Abstract: The evolution of the atherosclerotic plaque is regulated by the ability of its cells to dispose of excess cholesterol before apoptosis ensues. Macrophages are the dominant cell type of early plaques in humans and mice, and can utilize several pathways for lipoprotein internalization and for cholesterol efflux. Because cholesterol efflux is activated by delivery of lipoprotein-derived oxysterols to LXR, it is possible that different internalizing receptors may induce different macrophage responses to the same cholesterol load. Apolipoprotein (apo)E, a multifunctional protein highly expressed by macrophages and under LXR control, has strong anti-atherogenic effects that can be mediated by its interactions with internalizing receptors, such LDLR and LRP1, or with agents of cholesterol efflux, such as ABCA1 and PLTP. In the previous cycle of this grant, we discovered that LRP1 deletion from macrophages leads to increased apoE synthesis and, surprisingly, increased lesion formation. This suggests that apoE cannot exert its beneficial effects without LRP1. We also identified a functional interaction between apoE and LRP1 controlling the secretory efficiency of macrophage apoE, and determined that human apoE variants expressed by macrophages associate differently with LRP1 and have profoundly different effects on atherogenesis. Finally, we provided evidence for a role of apoE in macrophage cholesterol efflux even in the presence of excess amounts of apoAI, the canonical activator of the HDL pathway. Our results are compatible with a scenario where apoE and LRP1 work in a functional axis to maximize the adaptive responses of atheroma foam cells to the tremendous cholesterol burden in the arterial intima. In this new proposal, we plan to: 1) Demonstrate that the interaction between apoE and LRP1 in macrophages influences lesion formation in mouse models of atherosclerosis; 2) Test the hypothesis that LRP1-mediated internalization of apoE-enriched lipoproteins improves trafficking of cholesterol to efflux- accessible compartments and enhances LXR response; 3) Determine whether LRP1 signaling is responsible for anti-inflammatory and pro-survival counter-regulation in macrophages through cholesterol-dependent and independent mechanisms. Our studies aim at unlocking the fundamental regulation of cholesterol release from lesion macrophages into the HDL pathway as a platform for the development of therapeutics for plaque regression and control of ischemic heart disease. Our studies focus on the mechanisms leading to the accumulation and removal of cholesterol from the atherosclerotic plaque, which is the common cause of heart attacks and strokes. Whereas current medications can reduce the accumulation of cholesterol in the plaque by reducing plasma LDL levels, no therapies are available to induce exit of cholesterol from the plaque. We have discovered a functional connection between two proteins (apoE and LRP1) that improves cholesterol disposal in plaque macrophages, and may lead to development of new drugs for regression of coronary plaques.
Funding Period: 1998-01-01 - 2012-07-31
more information: NIH RePORT

Top Publications

  1. pmc Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice
    June Liu
    Department of Biochemistry and Molecular Biology, East Tennessee State University, Johnson City, TN 37614, USA
    Arterioscler Thromb Vasc Biol 25:174-9. 2005
  2. ncbi Angiotensin inhibition decreases progression of advanced atherosclerosis and stabilizes established atherosclerotic plaques
    Eisuke Suganuma
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232 2584, USA
    J Am Soc Nephrol 18:2311-9. 2007
  3. pmc Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus
    Aleksandar K Stanic
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 6300, USA
    Proc Natl Acad Sci U S A 103:7018-23. 2006
  4. ncbi Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction
    Eisuke Suganuma
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Am Soc Nephrol 17:433-41. 2006
  5. ncbi Macrophage apolipoprotein E reduces atherosclerosis and prevents premature death in apolipoprotein E and scavenger receptor-class BI double-knockout mice
    Hong Yu
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    Arterioscler Thromb Vasc Biol 26:150-6. 2006
  6. ncbi ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages
    Dwayne E Dove
    Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    Atherosclerosis 186:267-74. 2006
  7. ncbi Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice
    Michael E Burleigh
    Department of Pharmacology, 383 Preston Research Building, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    J Mol Cell Cardiol 39:443-52. 2005
  8. ncbi Transiently heightened angiotensin II has distinct effects on atherosclerosis and aneurysm formation in hyperlipidemic mice
    Nobuhiko Ayabe
    Department of Pediatrics, MCN C4204, Vanderbilt University Medical Center, Nashville, TN 37232 2584, USA
    Atherosclerosis 184:312-21. 2006
  9. ncbi A pathway-dependent on apoE, ApoAI, and ABCA1 determines formation of buoyant high-density lipoprotein by macrophage foam cells
    Patricia G Yancey
    Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn 37232 6300, USA
    Arterioscler Thromb Vasc Biol 27:1123-31. 2007
  10. pmc Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis
    Yan Ru Su
    Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN 37232 6300, USA
    Arterioscler Thromb Vasc Biol 28:1439-46. 2008

Scientific Experts

  • Vladimir R Babaev
  • Yan Ru Su
  • Patricia G Yancey
  • L Roberts
  • Alyssa Hasty
  • Sergio Fazio
  • Macrae F Linton
  • Dwayne E Dove
  • Daping Fan
  • Eisuke Suganuma
  • Nobuhiko Ayabe
  • Michael E Burleigh
  • Cheryl D Overton
  • Valentina Kon
  • Iekuni Ichikawa
  • Agnes B Fogo
  • Amy S Major
  • Larry L Swift
  • Wenwu Zhang
  • Ashwath Jayagopal
  • Shenfeng Qiu
  • Maria Gustafsson
  • Yiqin Zuo
  • Hong Yu
  • W Gray Jerome
  • Aleksandar K Stanic
  • John A Oates
  • Marnie L Gruen
  • June Liu
  • Jason D Morrow
  • John L Blakemore
  • Frederick R Haselton
  • Edwin J Weeber
  • Lei Ding
  • Clay F Semenkovich
  • Kristina Skålén
  • Vincent Fridén
  • Sven Olof Olofsson
  • Jeanna Perman
  • Pernilla Jirholt
  • Masaru Motojima
  • Jan Boren
  • Gunilla Olivecrona
  • Malin Levin
  • Edward K Wakeland
  • Mark J Koury
  • Yiwei Tang
  • Charles M Stein
  • Takakuni Tanizawa
  • Youmin Zhang
  • Adam C Morgan
  • Nancy J Olsen
  • Ji Ma
  • Mayur B Patel
  • Lawrence J Marnett
  • Michael S Sinensky
  • Jennifer L McCaleb
  • Douglas P Thewke
  • Rory P Remmel
  • Brenda C Crews
  • Michelle R Plummer
  • Kelly A Posey

Detail Information

Publications29

  1. pmc Reduced macrophage apoptosis is associated with accelerated atherosclerosis in low-density lipoprotein receptor-null mice
    June Liu
    Department of Biochemistry and Molecular Biology, East Tennessee State University, Johnson City, TN 37614, USA
    Arterioscler Thromb Vasc Biol 25:174-9. 2005
    ..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...
  2. ncbi Angiotensin inhibition decreases progression of advanced atherosclerosis and stabilizes established atherosclerotic plaques
    Eisuke Suganuma
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232 2584, USA
    J Am Soc Nephrol 18:2311-9. 2007
    ....
  3. pmc Immune dysregulation accelerates atherosclerosis and modulates plaque composition in systemic lupus erythematosus
    Aleksandar K Stanic
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 6300, USA
    Proc Natl Acad Sci U S A 103:7018-23. 2006
    ..Collectively, these studies demonstrate that the lupus-susceptible immune system enhances atherogenesis and modulates plaque composition...
  4. ncbi Antiatherogenic effects of angiotensin receptor antagonism in mild renal dysfunction
    Eisuke Suganuma
    Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    J Am Soc Nephrol 17:433-41. 2006
    ....
  5. ncbi Macrophage apolipoprotein E reduces atherosclerosis and prevents premature death in apolipoprotein E and scavenger receptor-class BI double-knockout mice
    Hong Yu
    Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    Arterioscler Thromb Vasc Biol 26:150-6. 2006
    ..The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice...
  6. ncbi ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages
    Dwayne E Dove
    Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    Atherosclerosis 186:267-74. 2006
    ..This change in cholesterol homeostasis may contribute to the atherogenic potential of ACAT1(-/-) macrophages...
  7. ncbi Cyclooxygenase-2 promotes early atherosclerotic lesion formation in ApoE-deficient and C57BL/6 mice
    Michael E Burleigh
    Department of Pharmacology, 383 Preston Research Building, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    J Mol Cell Cardiol 39:443-52. 2005
    ..These results are compatible with COX-2 expression by macrophages having a proatherogenic role, and support the potential of anti-inflammatory therapeutic approaches for atherosclerosis...
  8. ncbi Transiently heightened angiotensin II has distinct effects on atherosclerosis and aneurysm formation in hyperlipidemic mice
    Nobuhiko Ayabe
    Department of Pediatrics, MCN C4204, Vanderbilt University Medical Center, Nashville, TN 37232 2584, USA
    Atherosclerosis 184:312-21. 2006
    ..By contrast, transient AngII-exposure causes prompt aneurysm formation that does not parallel atherosclerosis and disappears even in the face of progressively greater atherosclerotic lesions...
  9. ncbi A pathway-dependent on apoE, ApoAI, and ABCA1 determines formation of buoyant high-density lipoprotein by macrophage foam cells
    Patricia G Yancey
    Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn 37232 6300, USA
    Arterioscler Thromb Vasc Biol 27:1123-31. 2007
    ..ABCA1-dependent and ABCA1-independent pathways may operate in high-density lipoprotein formation by macrophages secreting apolipoprotein (apo) E. We examined the impact of ABCA1 on apoE-mediated efflux from cholesterol-enriched macrophages...
  10. pmc Lentiviral transduction of apoAI into hematopoietic progenitor cells and macrophages: applications to cell therapy of atherosclerosis
    Yan Ru Su
    Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville TN 37232 6300, USA
    Arterioscler Thromb Vasc Biol 28:1439-46. 2008
    ..We used genetically engineered mouse hematopoietic progenitor cells (HPCs) to investigate the therapeutic effects of human apoAI on atherosclerosis in apoE(-/-) mice...
  11. ncbi The recycling of apolipoprotein E in macrophages: influence of HDL and apolipoprotein A-I
    Alyssa H Hasty
    Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    J Lipid Res 46:1433-9. 2005
    ..These results suggest that apoE recycling in macrophages may be part of a larger signaling loop activated by HDL and directed at maximizing cholesterol losses from the cell...
  12. ncbi Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1
    Yan Ru Su
    Atherosclerosis Research Unit, Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn 37232 6300, USA
    Circulation 111:2373-81. 2005
    ..We have studied the effect of macrophage ACAT1 deletion on atherogenesis in apoE-deficient (apoE-/-) mice with or without the restoration of macrophage apoE...
  13. pmc Self-association of human PCSK9 correlates with its LDLR-degrading activity
    Daping Fan
    Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6300, USA
    Biochemistry 47:1631-9. 2008
    ..These results provide a basis for developing strategies to manipulate PCSK9 activity in the circulation for the treatment of hypercholesterolemia...
  14. pmc The relationship between dose of vitamin E and suppression of oxidative stress in humans
    L Jackson Roberts
    Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA
    Free Radic Biol Med 43:1388-93. 2007
    ..This study provides information on the dosage of vitamin E that decreases systemic oxidant stress in vivo in humans and informs the planning and evaluation of clinical studies that assess the efficacy of vitamin E to mitigate disease...
  15. ncbi Macrophage expression of peroxisome proliferator-activated receptor-alpha reduces atherosclerosis in low-density lipoprotein receptor-deficient mice
    Vladimir R Babaev
    Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn, USA
    Circulation 116:1404-12. 2007
    ..PPARalpha ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARalpha expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes...
  16. pmc Macrophage EP4 deficiency increases apoptosis and suppresses early atherosclerosis
    Vladimir R Babaev
    Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 6300, USA
    Cell Metab 8:492-501. 2008
    ....
  17. ncbi Impaired secretion of apolipoprotein E2 from macrophages
    Daping Fan
    Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232 6300, USA
    J Biol Chem 282:13746-53. 2007
    ..Given the role of locally produced apoE in regulating cholesterol efflux, modulating inflammation, and controlling oxidative stress, this unique property of apoE2 may have important impacts on atherogenesis...
  18. ncbi Retention of low-density lipoprotein in atherosclerotic lesions of the mouse: evidence for a role of lipoprotein lipase
    Maria Gustafsson
    Sahlgrenska Center for Cardiovascular and Metabolic Research Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Goteborg University, Sweden
    Circ Res 101:777-83. 2007
    ..Thus, retention of LDL in the artery wall is initiated by direct LDL-proteoglycan binding but shifts to indirect binding with bridging molecules such as LPL...
  19. ncbi Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse
    Cheryl D Overton
    Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    Circ Res 100:670-7. 2007
    ..Our data support the hypothesis that macrophage LRP modulates atherogenesis through regulation of inflammatory responses...
  20. ncbi ACAT1 deficiency disrupts cholesterol efflux and alters cellular morphology in macrophages
    Dwayne E Dove
    Department of Pathology, Vanderbilt University Medical Center, Nashville, Tenn 37232 6300, USA
    Arterioscler Thromb Vasc Biol 25:128-34. 2005
    ..The objective of the current study was to elucidate the mechanism of the increased atherosclerosis...
  21. ncbi ApoE-mediated cholesterol efflux from macrophages: separation of autocrine and paracrine effects
    Dwayne E Dove
    Department of Pathology, Vanderbilt University Medical Center, 383 Preston Research Bldg, Nashville, TN 37232 6300, USA
    Am J Physiol Cell Physiol 288:C586-92. 2005
    ..Furthermore, autocrine effects of apoE could be critical in the prevention of foam cell formation in vivo. This novel methodology may be applicable to other types of mixed autocrine/paracrine systems, such as signal transduction systems...
  22. ncbi ACAT inhibition: bad for macrophages, good for smooth muscle cells?
    Sergio Fazio
    Arterioscler Thromb Vasc Biol 25:7-9. 2005
  23. ncbi Conditional knockout of macrophage PPARgamma increases atherosclerosis in C57BL/6 and low-density lipoprotein receptor-deficient mice
    Vladimir R Babaev
    Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    Arterioscler Thromb Vasc Biol 25:1647-53. 2005
    ..Peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in macrophage-derived foam cells of atherosclerotic lesions, and its expression may have a dramatic impact on atherosclerosis...
  24. ncbi Inhibition of cyclooxygenase with indomethacin phenethylamide reduces atherosclerosis in apoE-null mice
    Michael E Burleigh
    Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232 6300, USA
    Biochem Pharmacol 70:334-42. 2005
    ....
  25. ncbi Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I
    Marnie L Gruen
    Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232, USA
    J Lipid Res 46:2007-14. 2005
    ..Moreover, the presence of large HDLs without apoA-I provides evidence for an apoA-I-independent pathway of cholesterol efflux, possibly sustained by apoE...
  26. ncbi Cyclooxygenase-1 deficiency in bone marrow cells increases early atherosclerosis in apolipoprotein E- and low-density lipoprotein receptor-null mice
    Vladimir R Babaev
    Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    Circulation 113:108-17. 2006
    ..Here, we examined the impact of COX-1 deficiency in bone marrow-derived cells on early atherogenesis in the mouse...
  27. ncbi Severely altered cholesterol homeostasis in macrophages lacking apoE and SR-BI
    Patricia G Yancey
    Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
    J Lipid Res 48:1140-9. 2007
    ..Both factors are likely to contribute to the accelerated atherosclerosis in DKO mice...
  28. pmc Quantum dot mediated imaging of atherosclerosis
    Ashwath Jayagopal
    Department of Biomedical Engineering, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    Nanotechnology 20:165102. 2009
    ..It also has great utility in studies aimed at investigating the role of distinct circulating leukocyte subsets in plaque development and progression...