Mechanisms of Atherogenesis in Insulin Resistance

Summary

Principal Investigator: IRA A TABAS
Abstract: DESCRIPTION (provided by applicant): The epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complication, atherosclerotic cardiovascular disease (CVD). Thus, there is great interest in understanding the role of insulin resistance in both hepatic dyslipidemia, which triggers and maintains atherosclerosis, and in atherogenic events occurring in the plaque cells themselves. The proposed PPG will bring together experts in these different areas working towards a common goal and with a proven record of success over the last 5 years of funding. The overall theme of the PPG is to elucidate novel signal transduction pathways in the liver and in lesional macrophages (Mfs) and endothelial cells (ECs) that contribute to the dyslipidemia and accelerated atherosclerotic lesion progression in insulin-resistant states. In Project 1, Dr. Tabas will focus on the enzyme CaMKII, which has a critical role in (a) both basal and insulin resistance-exacerbated apoptosis of endoplasmic reticulum (ER)-stressed Mfs, which leads to plaque necrosis;and (b) in hepatic derived metabolic disturbances, including dyslipidemia and alterations in FoxO signaling, in obesity and insulin resistance. In Project 2, Dr. Tall will investigate the cellular-molecular mechanisms of hepatic-derived dyslipidemia in insulin resistance, with, emphasis on a novel mTORC1-Sortilin1 pathway that is relevant to recent human genetic studies and, as recent data shows, linked to ER stress and CaMKII. In Project 3, Dr. Accili will focus on vascular ECs as a key site of interaction between insulin resistance and hyperglycemia in atherosclerosis. The emphasis will be on how insulin resistance and hyperglycemia signal through the FoxO proteins to promote atherogenic processes in ECs. Each project will be supported by the Lesion Analysis/Biostatistics Core, in which Dr. Welch's team will provide assistance and expertise in atherosclerosis assays and in biomathematics. The common sub-themes among the projects include: (a) molecules and pathways involved in pro-atherogenic lesional cell dysfunction (Mfs, ECs), including FoxO's, ER stress, CaMKII, mTORC1 (all 3 projects);(b) pathways involved insulin resistance-induced dyslipidemia, including FoxO's, ER stress, mTORC1, Sortilin1, and CaMKII (Projects 1 and 2 in collaboration with Dr. Accili);and (c) mouse models of atherosclerotic lesion development and advanced plaque progression/plaque necrosis (all 3 projects and Core A). The synergistic and highly interactive nature of these projects and the complementary expertise in atherosclerosis and diabetes will enable a unique opportunity to address the emerging epidemic of insulin resistance-associated heart disease. (End of Abstract)
Funding Period: 2006-12-01 - 2018-01-31
more information: NIH RePORT

Top Publications

  1. pmc Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity
    Prabhakara R Nagareddy
    Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA
    Cell Metab 19:821-35. 2014
  2. pmc Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice
    Ding Ai
    Department of Medicine, Columbia University, New York, New York 10032, USA
    J Clin Invest 122:1262-70. 2012
  3. pmc FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis
    Kyoichiro Tsuchiya
    Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 15:372-81. 2012
  4. pmc Increased atherosclerosis and endothelial dysfunction in mice bearing constitutively deacetylated alleles of Foxo1 gene
    Li Qiang
    Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA
    J Biol Chem 287:13944-51. 2012
  5. pmc FGF21 and the second coming of PPARγ
    Li Qiang
    Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Cell 148:397-8. 2012
  6. pmc Role of endoplasmic reticulum stress in metabolic disease and other disorders
    Lale Ozcan
    Department of Medicine, Columbia University, New York, New York 10032, USA
    Annu Rev Med 63:317-28. 2012
  7. pmc Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia
    Rebecca A Haeusler
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell Metab 15:65-74. 2012
  8. pmc Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation
    Li Qiang
    Naomi Berrie Diabetes Center, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 14:758-67. 2011
  9. pmc Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice
    Alexander S Banks
    Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 14:587-97. 2011
  10. pmc Insulin resistance, hyperglycemia, and atherosclerosis
    Karin E Bornfeldt
    Department of Pathology, Diabetes and Obesity Center of Excellence, 815 Mercer Street, University of Washington, Seattle, WA 98109, USA
    Cell Metab 14:575-85. 2011

Research Grants

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
  2. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
  3. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013

Detail Information

Publications54

  1. pmc Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity
    Prabhakara R Nagareddy
    Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA
    Cell Metab 19:821-35. 2014
    ..These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity. ..
  2. pmc Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice
    Ding Ai
    Department of Medicine, Columbia University, New York, New York 10032, USA
    J Clin Invest 122:1262-70. 2012
    ..We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy...
  3. pmc FoxOs integrate pleiotropic actions of insulin in vascular endothelium to protect mice from atherosclerosis
    Kyoichiro Tsuchiya
    Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 15:372-81. 2012
    ..The data demonstrate that FoxO inhibition in endothelial cells has the potential to mediate wide-ranging therapeutic benefits for diabetes-associated cardiovascular disease...
  4. pmc Increased atherosclerosis and endothelial dysfunction in mice bearing constitutively deacetylated alleles of Foxo1 gene
    Li Qiang
    Berrie Diabetes Center and Department of Medicine, Columbia University, New York, New York 10032, USA
    J Biol Chem 287:13944-51. 2012
    ..The data indicate that FoxO1 deacetylation can promote vascular endothelial changes conducive to atherosclerotic plaque formation...
  5. pmc FGF21 and the second coming of PPARγ
    Li Qiang
    Department of Medicine and Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
    Cell 148:397-8. 2012
    ..Does this new property improve FGF21's fledgling clinical prospects or endorse a clinical resuscitation of PPARγ agonists?..
  6. pmc Role of endoplasmic reticulum stress in metabolic disease and other disorders
    Lale Ozcan
    Department of Medicine, Columbia University, New York, New York 10032, USA
    Annu Rev Med 63:317-28. 2012
    ..With the improved understanding of the underlying molecular mechanisms, therapeutic interventions that target the ER stress response would be potential strategies to treat various diseases driven by prolonged ER stress...
  7. pmc Impaired generation of 12-hydroxylated bile acids links hepatic insulin signaling with dyslipidemia
    Rebecca A Haeusler
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell Metab 15:65-74. 2012
    ..We propose that generation of 12α-hydroxylated products of BA metabolism represents a signaling mechanism linking hepatic lipid abnormalities with type 2 diabetes, and a treatment target for this condition...
  8. pmc Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation
    Li Qiang
    Naomi Berrie Diabetes Center, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 14:758-67. 2011
    ..We propose that SirT1-dependent Creb deacetylation regulates the balance between glucose and lipid metabolism, integrating fasting signals...
  9. pmc Dissociation of the glucose and lipid regulatory functions of FoxO1 by targeted knockin of acetylation-defective alleles in mice
    Alexander S Banks
    Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 14:587-97. 2011
    ..Thus, acetylation inactivates FoxO1 during nutrient excess whereas deacetylation selectively potentiates FoxO1 activity, protecting against excessive catabolism during nutrient deprivation...
  10. pmc Insulin resistance, hyperglycemia, and atherosclerosis
    Karin E Bornfeldt
    Department of Pathology, Diabetes and Obesity Center of Excellence, 815 Mercer Street, University of Washington, Seattle, WA 98109, USA
    Cell Metab 14:575-85. 2011
    ..Understanding the mechanisms whereby type 2 diabetes exacerbates CAD offers hope for new therapeutic strategies to prevent and treat atherosclerotic vascular disease...
  11. pmc Homozygosity for an allele encoding deacetylated FoxO1 protects macrophages from cholesterol-induced inflammation without increasing apoptosis
    Kyoichiro Tsuchiya
    Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY, USA
    Arterioscler Thromb Vasc Biol 31:2920-8. 2011
    ..We sought to identify the mechanism whereby FoxO1 dampens inflammation without promoting apoptosis. We hypothesized that nutrient-dependent FoxO1 acetylation plays a role in this process...
  12. pmc Activation of ER stress and mTORC1 suppresses hepatic sortilin-1 levels in obese mice
    Ding Ai
    Department of Medicine, Columbia University, New York, New York 10032, USA
    J Clin Invest 122:1677-87. 2012
    ..Thus, in mouse models of obesity, induction of mTORC1 and ER stress led to repression of hepatic Sort1 and increased VLDL secretion via Atf3. This pathway may contribute to dyslipidemia in metabolic disease...
  13. pmc Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes
    Yiguo Wang
    Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA
    Nature 485:128-32. 2012
    ....
  14. pmc Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity
    Lale Ozcan
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell Metab 15:739-51. 2012
    ..This same pathway is also involved in excessive HGP in the setting of obesity. These results reveal a calcium-mediated signaling pathway involved in FoxO1 nuclear localization and hepatic glucose homeostasis...
  15. pmc Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis
    Ding Ai
    From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY D A, H J, M Westerterp, A J M, M Wang, A G, S A, C W, A R T Department of Physiology, Tianjin Medical University, Tianjin, China D A, Y Z Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands M Westerterp and Department of Medicine, University of California at San Diego, CA F A, Y I M
    Circ Res 114:1576-84. 2014
    ..This suggests an antiatherogenic effect possibly mediated by the modulation of inflammatory responses in atherosclerotic plaques...
  16. pmc Activation of calcium/calmodulin-dependent protein kinase II in obesity mediates suppression of hepatic insulin signaling
    Lale Ozcan
    Department of Medicine, Columbia University, New York, NY 10032, USA Electronic address
    Cell Metab 18:803-15. 2013
    ..These findings increase our understanding of the molecular mechanisms linking obesity to selective insulin resistance and suggest new therapeutic targets for type 2 diabetes and metabolic syndrome. ..
  17. pmc Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis
    Prabhakara R Nagareddy
    Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell Metab 17:695-708. 2013
    ..In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes...
  18. pmc Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity
    Andrew J Murphy
    Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA
    Circ Res 113:e1-9. 2013
    ..However, rapid clearance leads to a requirement for repeated administration of large amounts of material and limits effective plasma concentrations...
  19. pmc Expanded granulocyte/monocyte compartment in myeloid-specific triple FoxO knockout increases oxidative stress and accelerates atherosclerosis in mice
    Kyoichiro Tsuchiya
    Naomi Berrie Diabetes Center, 1150 St Nicholas Ave, Russ Berrie Pavilion Room 238, NY 10032, USA
    Circ Res 112:992-1003. 2013
    ..Increased neutrophil and monocyte counts are often associated with an increased risk of atherosclerosis, but their relationship to insulin sensitivity is unknown...
  20. pmc Liver sinusoidal endothelial cells link hyperinsulinemia to hepatic insulin resistance
    Kyoichiro Tsuchiya
    Naomi Berrie Diabetes Center and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA
    Diabetes 62:1478-89. 2013
    ..The findings are consistent with a model in which excessive, rather than reduced, insulin signaling in ECs predisposes to systemic insulin resistance, prompting a reevaluation of current approaches to insulin sensitization...
  21. pmc Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure
    Chutima Talchai
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell 150:1223-34. 2012
    ..We propose that dedifferentiation trumps endocrine cell death in the natural history of β cell failure and suggest that treatment of β cell dysfunction should restore differentiation, rather than promoting β cell replication...
  22. pmc Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ
    Li Qiang
    Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell 150:620-32. 2012
    ..We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import...
  23. pmc Impaired MEK signaling and SERCA expression promote ER stress and apoptosis in insulin-resistant macrophages and are reversed by exenatide treatment
    Chien Ping Liang
    Department of Medicine, Columbia University, New York, New York, USA
    Diabetes 61:2609-20. 2012
    ..Increased signaling via GLP-1 receptor or the CREBP activator protein kinase A thus offers a way to rescue insulin-resistant macrophages from excessive ER stress responses and apoptosis in insulin resistance and type 2 diabetes...
  24. pmc FoxO1 target Gpr17 activates AgRP neurons to regulate food intake
    Hongxia Ren
    Berrie Diabetes Center, Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell 149:1314-26. 2012
    ..These effects are absent in Agrp-Foxo1 knockouts, suggesting that pharmacological modulation of this pathway has therapeutic potential to treat obesity...
  25. pmc The LPS2 mutation in TRIF is atheroprotective in hyperlipidemic low density lipoprotein receptor knockout mice
    M Rachel Richards
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
    Innate Immun 19:20-9. 2013
    ..Collectively, these data suggest that hyperlipidemia resulting in endogenous activation of the TRIF signaling pathway from TLR4 leads to pro-atherogenic events...
  26. pmc Hormonal regulation of hepatic glucose production in health and disease
    Hua V Lin
    Merck Research Laboratories, Rahway, NJ 07065, USA
    Cell Metab 14:9-19. 2011
    ..A clinical hallmark of diabetes, excessive glucose production remains key to its treatment. Hence, we attempt to integrate emerging pathways into the broader goal to rejuvenate the staid antidiabetic pharmacopeia...
  27. pmc Macrophages in the pathogenesis of atherosclerosis
    Kathryn J Moore
    Department of Medicine, New York University Medical Center, NY 10016, USA
    Cell 145:341-55. 2011
    ..This Review discusses the central roles of macrophages in each of these stages of disease pathogenesis...
  28. pmc Foxo1 links hyperglycemia to LDL oxidation and endothelial nitric oxide synthase dysfunction in vascular endothelial cells
    Jun Tanaka
    Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York, USA
    Diabetes 58:2344-54. 2009
    ..Biochemical mechanism leading from hyperglycemia to oxLDL formation and eNOS dysfunction is unknown...
  29. pmc Macrophage deficiency of p38alpha MAPK promotes apoptosis and plaque necrosis in advanced atherosclerotic lesions in mice
    Tracie A Seimon
    Department of Medicine, Division of Molecular Medicine, Columbia University, PH 9 405, 630 W 168th Street, New York, New York 10032, USA
    J Clin Invest 119:886-98. 2009
    ..Our results demonstrate that p38alpha MAPK may play a critical role in suppressing ER stress-induced macrophage apoptosis in vitro and advanced lesional macrophage apoptosis in vivo...
  30. pmc Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice
    Seongah Han
    Division of Molecular Medicine, Department of Medicine, Columbia University, 630 West 168th St, New York, New York 10032, USA
    J Clin Invest 119:1029-41. 2009
    ..These findings suggest a dual action of hepatic IR on lipoprotein levels, in which the ability to increase VLDL apoB and lipid secretion via AKT/GSK is offset by upregulation of Ldlr...
  31. pmc Free cholesterol accumulation in macrophage membranes activates Toll-like receptors and p38 mitogen-activated protein kinase and induces cathepsin K
    Yu Sun
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Circ Res 104:455-65. 2009
    ....
  32. pmc Mechanisms and consequences of macrophage apoptosis in atherosclerosis
    Tracie Seimon
    Department of Medicine, Columbia University, New York, NY 10032, USA
    J Lipid Res 50:S382-7. 2009
    ..Of particular interest is the complex and coordinated role that the endoplasmic reticulum (ER) stress pathway and pattern recognition receptors (PRRs) may play in triggering macrophage apoptosis...
  33. pmc Loss of SR-A and CD36 activity reduces atherosclerotic lesion complexity without abrogating foam cell formation in hyperlipidemic mice
    Jennifer J Manning-Tobin
    Lipid Metabolism Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA
    Arterioscler Thromb Vasc Biol 29:19-26. 2009
    ..To test the impact of deleting these receptors, we generated Apoe(-/-) mice lacking both SR-A and CD36 and fed them a Western diet for 12 weeks...
  34. pmc Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin-6/STAT3 signaling mechanism
    Yankun Li
    Department of Medicine, Columbia University, New York, New York 10032, USA
    J Biol Chem 283:34833-43. 2008
    ..These data suggest a novel action and mechanism of eNampt that could affect the balance of macrophage survival and death in the setting of obesity, which in turn could play important roles in obesity-associated diseases...
  35. pmc SirT1 gain of function increases energy efficiency and prevents diabetes in mice
    Alexander S Banks
    Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
    Cell Metab 8:333-41. 2008
    ..These findings have important implications for Sirtuin-based therapies in humans...
  36. pmc Forkhead transcription factors (FoxOs) promote apoptosis of insulin-resistant macrophages during cholesterol-induced endoplasmic reticulum stress
    Takafumi Senokuchi
    Department of Medicine, Columbia University, New York, New York, USA
    Diabetes 57:2967-76. 2008
    ..However, the molecular mechanisms of increased apoptosis in insulin-resistant macrophages remain unclear...
  37. pmc The impact of insulin resistance on macrophage death pathways in advanced atherosclerosis
    Ira Tabas
    Department of Medicine, 630 West 168th Street, Columbia University, New York, NY 10032, USA
    Novartis Found Symp 286:99-109; discussion 109-12, 162-3, 196-203. 2007
    ....
  38. pmc 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
    Wah Seng Lim
    Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032, USA
    Circulation 117:940-51. 2008
    ....
  39. pmc Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrial apoptosis pathways
    Jenelle M Timmins
    Department of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, USA
    J Clin Invest 119:2925-41. 2009
    ..These findings raise the possibility that CaMKII inhibitors could be useful in preventing apoptosis in pathological settings involving ER stress-induced apoptosis...
  40. pmc Macrophage apoptosis in advanced atherosclerosis
    Ira Tabas
    Department of Medicine, Columbia University Medical Center, New York, New York, USA
    Ann N Y Acad Sci 1173:E40-5. 2009
    ..Further understanding of the mechanisms and consequences of this event may lead to novel therapies directed at preventing the clinical progression of atheromata...
  41. pmc Role of ERO1-alpha-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis
    Gang Li
    Department of Medicine, Columbia University, New York, NY 10032, USA
    J Cell Biol 186:783-92. 2009
    ..Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-alpha-IP3R pathway...
  42. pmc Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress
    Ira Tabas
    Department of Medicine, Anatomy and Cell Biology, Columbia University, New York, NY 10032, USA
    Nat Cell Biol 13:184-90. 2011
    ..The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress...
  43. pmc NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
    Gang Li
    Department of Medicine, Columbia University, New York, NY 10032, USA
    J Cell Biol 191:1113-25. 2010
    ..These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner...
  44. pmc Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress
    Tracie A Seimon
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Cell Metab 12:467-82. 2010
    ..These findings provide insight into how atherogenic lipoproteins trigger macrophage apoptosis in the setting of ER stress and how TLR activation might promote macrophage apoptosis and plaque necrosis in advanced atherosclerosis...
  45. pmc n-3 Fatty acids decrease arterial low-density lipoprotein cholesterol delivery and lipoprotein lipase levels in insulin-resistant mice
    Chuchun L Chang
    Institute of Human Nutrition, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
    Arterioscler Thromb Vasc Biol 30:2510-7. 2010
    ..To determine whether n-3 fatty acids (n-3) influence arterial cholesterol delivery and lipoprotein lipase (LpL) levels in insulin-resistant mice...
  46. pmc The role of endoplasmic reticulum stress in the progression of atherosclerosis
    Ira Tabas
    Department of Medicine, Columbia University, New York, NY 10032, USA
    Circ Res 107:839-50. 2010
    ....
  47. pmc FoxOs function synergistically to promote glucose production
    Rebecca A Haeusler
    Department of Medicine, Columbia University, New York, New York 10032, USA
    J Biol Chem 285:35245-8. 2010
    ..In contrast, combined ablation of FoxO1 and FoxA2 phenocopied the single knock-out of FoxO1. These data indicate that FoxOs work in concert to regulate multiple aspects of hepatic glucose metabolism...
  48. pmc Hepatic FoxO1 ablation exacerbates lipid abnormalities during hyperglycemia
    Rebecca A Haeusler
    Department of Medicine, Columbia University, New York, New York 10032, USA
    J Biol Chem 285:26861-8. 2010
    ....
  49. pmc Lack of association between adiponectin levels and atherosclerosis in mice
    Andrea R Nawrocki
    Department of Obesity, Merck Research Laboratories, Rahway, New Jersey, USA
    Arterioscler Thromb Vasc Biol 30:1159-65. 2010
    ..Adiponectin has been associated with antiinflammatory and antiatherogenic properties; however, the direct involvement of adiponectin on the atherogenic process has not been studied...
  50. pmc The impact of macrophage insulin resistance on advanced atherosclerotic plaque progression
    Ira Tabas
    Department of Medicine, Columbia University, 630 West 168th St, New York, NY 10032, USA
    Circ Res 106:58-67. 2010
    ..These processes may therefore provide an important mechanistic link among insulin resistance, plaque necrosis, and atherothrombotic vascular disease and suggest novel therapeutic approaches to this expanding health problem...
  51. pmc Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet
    Suzhao Li
    Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA
    Circ Res 105:1072-82. 2009
    ..Defective clearance of apoptotic cells by macrophages (efferocytosis) is thought to lead to increased necrotic core formation and inflammation in atherosclerotic lesions...
  52. ncbi Apoptosis and efferocytosis in mouse models of atherosclerosis
    Ira Tabas
    Departments of Medicine, Pathology and Cell Biology, and Physiology and Cellular Biophysics I T, Columbia University, New York, NY 10032, USA
    Curr Drug Targets 8:1288-96. 2007
    ..Advances in these areas offer great hope for eventual translation into innovative therapeutic strategies to combat atherothrombotic vascular disease...

Research Grants30

  1. CARDIOVASCULAR DYNAMICS AND THEIR CONTROL
    John E Hall; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  3. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..