RAGE and Mechanisms of Vascular Dysfunction

Summary

Principal Investigator: Shi Fang Yan
Abstract: DESCRIPTION (provided by applicant): The homozygous RAGE null mouse formed the centerpiece of discoveries during the last cycle of this Program. We demonstrated that RAGE plays critical roles in atheroscierosis in apoE null mice, mediates upregulation of pro-inflammatory and tissue-destructive genes in hypoxia, and mediates loss of cardiac function in the heart upon ischemia/reperfusion (l/R). Multiple novel findings shape the direction of our Program: first, we discovered that the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin homology domain protein family and an effector of RhoGTPases. mDia-1 is essential for RAGE ligand-mediated cellular migration and activation of cdc42/rac-1. New discoveries link mDial to key properties of smooth muscle cells, macrophages and cardiomyocyte signaling. Second, Project 2 has discovered the unanticipated finding that RAGE plays opposing roles in acute vs. chronic hypoxia/ischemia on regulation of Egr-1 in endothelial cells and monocytes/macrophages. Third, Project 1 has discovered that RAGE downregulates ABCG1 and cholesterol efflux to HDL. Fourth, Project 3 has discovered that deletion of mDial is highly protective in the heart in l/R. As a Program, we have shared not merely tools and strategies by virtue of our Core units but, more importantly, we have sought to understand the "big picture" of RAGE signaling. As our data unfold, we recognize that RAGE signaling is not "one size fits all," as new discoveries have uncovered distinct pathways of regulation by the receptor depending on cell type, duration of stress, and specific form of cellular stress. The challenge is to put it together. Toward this end, we have generated novel RAGE- and mDial floxed to probe cell-specific signaling of this axis in atherosclerosis (Project 1), angiogenesis (Project 2) and myocardial infarction (Project 3). Taken together, these discoveries form the basis of a highly innovative and significant set of questions testing RAGE and mDial signaling in vascular dysfunction in diabetic- and non-diabetic cardiovascular pathology. Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program.
Funding Period: 1999-02-01 - 2017-11-30
more information: NIH RePORT

Top Publications

  1. ncbi RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes
    Thoralf Wendt
    Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W, 168th Street, Black Building 1705, New York, NY 10032, USA
    Atherosclerosis 185:70-7. 2006
  2. pmc Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model
    Ravichandran Ramasamy
    Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Circ Res 106:1449-58. 2010
  3. pmc Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages
    Yunlu Xu
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA
    J Biol Chem 285:23233-40. 2010
  4. pmc Reduction of PKCbetaII activity in smooth muscle cells attenuates acute arterial injury
    Chun Huang
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA
    Atherosclerosis 212:123-30. 2010
  5. pmc Human vascular endothelial cells: a model system for studying vascular inflammation in diabetes and atherosclerosis
    Duygu Onat
    Department of Medicine, Division of Cardiology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West, 168th Street, PS 17 401, New York, NY 10032, USA
    Curr Diab Rep 11:193-202. 2011
  6. pmc Aldose reductase pathway contributes to vulnerability of aging myocardium to ischemic injury
    Radha Ananthakrishnan
    Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA
    Exp Gerontol 46:762-7. 2011
  7. pmc Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice
    Srinivasan Vedantham
    Division of Endocrinology, New York University Langone Medical Center, NY 10016, USA
    Arterioscler Thromb Vasc Biol 31:1805-13. 2011
  8. pmc Imaging of receptors for advanced glycation end products in experimental myocardial ischemia and reperfusion injury
    Yared Tekabe
    Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA
    JACC Cardiovasc Imaging 5:59-67. 2012
  9. pmc Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways
    Fatouma Toure
    Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
    Circ Res 110:1279-93. 2012
  10. pmc Aldose reductase, oxidative stress and diabetic cardiovascular complications
    Srinivasan Vedantham
    Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA
    Cardiovasc Hematol Agents Med Chem 10:234-40. 2012

Detail Information

Publications38

  1. ncbi RAGE modulates vascular inflammation and atherosclerosis in a murine model of type 2 diabetes
    Thoralf Wendt
    Department of Surgery, College of Physicians and Surgeons of Columbia University, 630 W, 168th Street, Black Building 1705, New York, NY 10032, USA
    Atherosclerosis 185:70-7. 2006
    ..Taken together, these findings establish a new murine model for the study of atherosclerosis in type 2 diabetes and highlight important roles for RAGE in proatherogenic mechanisms in hyperglycemia triggered by insulin resistance...
  2. pmc Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model
    Ravichandran Ramasamy
    Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Circ Res 106:1449-58. 2010
    ..For AR, this will require tissue specific expression of AR in sites and at levels that approximate those in humans...
  3. pmc Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages
    Yunlu Xu
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York 10032, USA
    J Biol Chem 285:23233-40. 2010
    ..Our findings highlight a novel mechanism by which an extracellular signal initiated by RAGE ligand AGEs regulates Egr-1 in a manner requiring mDia-1...
  4. pmc Reduction of PKCbetaII activity in smooth muscle cells attenuates acute arterial injury
    Chun Huang
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA
    Atherosclerosis 212:123-30. 2010
    ....
  5. pmc Human vascular endothelial cells: a model system for studying vascular inflammation in diabetes and atherosclerosis
    Duygu Onat
    Department of Medicine, Division of Cardiology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West, 168th Street, PS 17 401, New York, NY 10032, USA
    Curr Diab Rep 11:193-202. 2011
    ..In this article, we appraise the use of endothelial cell-based methodologies to study vascular inflammation in diabetes and atherosclerosis...
  6. pmc Aldose reductase pathway contributes to vulnerability of aging myocardium to ischemic injury
    Radha Ananthakrishnan
    Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA
    Exp Gerontol 46:762-7. 2011
    ..These data indicate that innate increases in activity of the PP enzymes augment myocardial vulnerability to I/R injury in aging, and that blockers of PP protect the vulnerable aging hearts...
  7. pmc Human aldose reductase expression accelerates atherosclerosis in diabetic apolipoprotein E-/- mice
    Srinivasan Vedantham
    Division of Endocrinology, New York University Langone Medical Center, NY 10016, USA
    Arterioscler Thromb Vasc Biol 31:1805-13. 2011
    ..The polyol pathway mediated by aldose reductase (AR) has been postulated to be one such pathway. However, it has been reported that AR reduces toxic lipid aldehydes and, under some circumstances, might be antiatherogenic...
  8. pmc Imaging of receptors for advanced glycation end products in experimental myocardial ischemia and reperfusion injury
    Yared Tekabe
    Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA
    JACC Cardiovasc Imaging 5:59-67. 2012
    ..The aim of this study was to image expression of receptor for advanced glycation end products (RAGE) in a mouse model of myocardial reperfusion injury...
  9. pmc Formin mDia1 mediates vascular remodeling via integration of oxidative and signal transduction pathways
    Fatouma Toure
    Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
    Circ Res 110:1279-93. 2012
    ....
  10. pmc Aldose reductase, oxidative stress and diabetic cardiovascular complications
    Srinivasan Vedantham
    Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY 10016, USA
    Cardiovasc Hematol Agents Med Chem 10:234-40. 2012
    ..Stopping AR-dependent signaling may hold the key to interrupting cycles of cellular perturbation and tissue damage in diabetic cardiovascular complications...
  11. pmc Aldose reductase modulates cardiac glycogen synthase kinase-3β phosphorylation during ischemia-reperfusion
    Mariane Abdillahi
    Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, USA
    Am J Physiol Heart Circ Physiol 303:H297-308. 2012
    ..In summary, AR mediates changes in p-GSK3β, in part, via PKCα/β and Akt during I/R...
  12. pmc Glycation and insulin resistance: novel mechanisms and unique targets?
    Fei Song
    Division of Endocrinology, Department of Medicine, New York University School of Medicine, 550 First Ave, Smilow 901C, New York, NY 10016, USA
    Arterioscler Thromb Vasc Biol 32:1760-5. 2012
    ..Strategies to limit AGE accumulation and action may contribute to the prevention of insulin resistance and its consequences...
  13. pmc Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling
    Vivek Rai
    Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA
    J Exp Med 209:2339-50. 2012
    ..These findings identify novel roles for RAGE as a conduit for LPA signaling and suggest targeting LPA-RAGE interaction as a therapeutic strategy to modify the pathological actions of LPA...
  14. pmc PKCβ promotes vascular inflammation and acceleration of atherosclerosis in diabetic ApoE null mice
    Linghua Kong
    Diabetes Research Program, Division of Endocrinology, Department of Medicine, NYU School of Medicine, New York, NY 10016, USA
    Arterioscler Thromb Vasc Biol 33:1779-87. 2013
    ..Because the metabolism of glucose results in production of activators of protein kinase C (PKC)β, it was logical to investigate the role of PKCβ in modulation of atherosclerosis in diabetes mellitus...
  15. pmc Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals
    Srinivasan Vedantham
    Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY
    Diabetes 63:761-74. 2014
    ..In conclusion, our data demonstrate a novel mechanism by which glucose flux via AR triggers activation, acetylation, and prolonged expression of Egr-1 leading to proinflammatory and prothrombotic responses in diabetic atherosclerosis. ..
  16. pmc RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice
    Fei Song
    Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY
    Diabetes 63:1948-65. 2014
    ....
  17. pmc RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3beta signaling pathways
    Linshan Shang
    Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America
    PLoS ONE 5:e10092. 2010
    ..In the current study, adult cardiomyocytes were studied in an in vitro ischemia/reperfusion (I/R) injury model to delineate the molecular mechanisms underlying RAGE-mediated injury due to hypoxia/reoxygenation (H/R)...
  18. pmc Activation of the ROCK1 branch of the transforming growth factor-beta pathway contributes to RAGE-dependent acceleration of atherosclerosis in diabetic ApoE-null mice
    De xiu Bu
    Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA
    Circ Res 106:1040-51. 2010
    ..The multiligand RAGE (receptor for advanced glycation end products) contributes to atherosclerosis in apolipoprotein (Apo)E-null mice...
  19. ncbi Receptor for advanced-glycation end products: key modulator of myocardial ischemic injury
    Loredana G Bucciarelli
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY 10032, USA
    Circulation 113:1226-34. 2006
    ..In this context, our laboratory has been investigating the role of the receptor for advanced-glycation end products (RAGE) in myocardial I/R injury...
  20. ncbi The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock
    Kathleen G Raman
    Univ of Pittsburgh School of Medicine, 616 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15213, USA
    Am J Physiol Gastrointest Liver Physiol 291:G556-65. 2006
    ..Circulating IL-10 levels were higher in rage(-/-) compared with rage(+/+) mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R...
  21. ncbi Sphingosine-1-phosphate: waging a battle in the diabetic blood vessel
    Ravichandran Ramasamy
    Circ Res 99:669-71. 2006
  22. ncbi Protein kinase C beta/early growth response-1 pathway: a key player in ischemia, atherosclerosis, and restenosis
    Shi Fang Yan
    Division of Surgical Science, Department of Surgery, Columbia University, New York, New York 10032, USA
    J Am Coll Cardiol 48:A47-55. 2006
    ....
  23. ncbi Blockade of RAGE suppresses alloimmune reactions in vitro and delays allograft rejection in murine heart transplantation
    B Moser
    Department of Surgery, Columbia University Medical Center, New York, New York, USA corrected
    Am J Transplant 7:293-302. 2007
    ..These data provide the first insights into key roles for RAGE in allorecognition responses and suggest that antagonism of this receptor may exert beneficial effects in allogeneic organ transplantation...
  24. ncbi PKCbeta modulates ischemia-reperfusion injury in the heart
    Linghua Kong
    Dept of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Am J Physiol Heart Circ Physiol 294:H1862-70. 2008
    ..These data implicate PKCbeta in I/R-mediated myocardial injury, at least in part via phosphorylation of JNK, and suggest that blockade of PKCbeta may represent a potent strategy to protect the vulnerable myocardium...
  25. ncbi RAGE modulates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model
    Alexey Aleshin
    Department of Surgery, Columbia University, New York, NY 10032, USA
    Am J Physiol Heart Circ Physiol 294:H1823-32. 2008
    ....
  26. pmc RAGE and modulation of ischemic injury in the diabetic myocardium
    Loredana G Bucciarelli
    Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, New York, USA
    Diabetes 57:1941-51. 2008
    ..In diabetic rat hearts, expression of RAGE and its ligands was enhanced and localized particularly to both endothelial cells and mononuclear phagocytes...
  27. pmc RAGE ligation affects T cell activation and controls T cell differentiation
    Yali Chen
    Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
    J Immunol 181:4272-8. 2008
    ..We conclude that activation of RAGE on T cells is involved in early events that lead to differentiation of Th1(+) T cells...
  28. pmc Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42
    Barry I Hudson
    Division of Surgical Science, Departments of Surgery and Pathology, Columbia University Medical Center, Columbia University, New York, New York, 10032, USA
    J Biol Chem 283:34457-68. 2008
    ....
  29. pmc Mice deficient in PKCbeta and apolipoprotein E display decreased atherosclerosis
    Evis Harja
    Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    FASEB J 23:1081-91. 2009
    ..Blockade of PKCbeta may be beneficial in mitigating endothelial perturbation and atherosclerosis...
  30. pmc Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore
    Radha Ananthakrishnan
    Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, NY, USA
    Am J Physiol Heart Circ Physiol 296:H333-41. 2009
    ..Therefore, inhibition of AR pathway protects mitochondria and hence may be a useful adjunct for salvaging ischemic myocardium...
  31. pmc Receptor for AGE (RAGE) and its ligands-cast into leading roles in diabetes and the inflammatory response
    Shi Fang Yan
    Department of Surgery, Columbia University, New York, NY 10032, USA
    J Mol Med (Berl) 87:235-47. 2009
    ..Targeting RAGE may be a beneficial strategy in diabetes, its complications, and untoward inflammatory responses...
  32. pmc The receptor for advanced glycation endproducts (RAGE) and cardiovascular disease
    Shi Fang Yan
    Division of Surgical Science, Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Expert Rev Mol Med 11:e9. 2009
    ..In this review, we focus on RAGE and the consequences of its activation in the cardiovasculature...
  33. pmc Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation
    Shi Fang Yan
    Division of Surgical Science, Department of Surgery, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA
    Ann Med 41:408-22. 2009
    ..As RAGE blockade moves further into clinical development, clarifying the biology of RAGE garners ever-increasing importance...
  34. pmc Novel role for aldose reductase in mediating acute inflammatory responses in the lung
    Thyyar M Ravindranath
    Department of Surgery, Columbia University, New York, NY 10032, USA
    J Immunol 183:8128-37. 2009
    ..These data demonstrate a novel role for AR in regulating the signaling pathways leading to neutrophil-EC adhesion during acute lung inflammation...
  35. pmc Soluble RAGE: therapy and biomarker in unraveling the RAGE axis in chronic disease and aging
    Shi Fang Yan
    Department of Surgery, Columbia University, New York, NY 10032, United States
    Biochem Pharmacol 79:1379-86. 2010
    ..In this article, we review the evidence from the rodent to the human implicating RAGE in the diverse disease states in which its ligands accumulate...