The Pathobiology of Macrovascular Disease in Diabetes Program Project

 

The Pathobiology of Macrovascular Disease in Diabetes Program Project (P01 HL092969) is funded by the National Heart, Lung, and Blood Institute of the NIH.  This Program Project Grant (PPG) was established in 1958 with Dr. Robert H. Williams as Program Director.  Dr. Edwin L. Bierman created the focus on lipids, lipoproteins, and cardiovascular disease associated with diabetes when he became PI of the PPG in 1975.  Dr. Alan Chait served as Program Director from 1995 to 2012, when Dr. Karin E. Bornfeldt took over the directorship of the Program.

Cardiovascular disease caused by lesions of atherosclerosis in the blood vessel wall is the most devastating complication of diabetes, increasing the risk of heart attack or stroke. The objective of this PPG is centered on identifying cellular and molecular mechanisms of the increased cardiovascular (macrovascular) complications associated with diabetes that may be amenable to preventive and therapeutic measures.  The expertise of our team in different areas relating to cardiovascular disease associated with diabetes ensures synergy and cross-fertilization among projects, which are likely to markedly advance research and identify new drug targets to combat macrovascular complications of diabetes.

Development of a lesion of atherosclerosis throughout a blood vessel
Development of a lesion of atherosclerosis Section of a blood vessel (the brachiocephalic artery) from a mouse with atherosclerosis. Formation of a lesion of atherosclerosis begins as an accumulation of immune cells (macrophages – stained light purple) in the blood vessel wall (left). The normal vascular wall consists of smooth muscle cells (red) held together by elastin filaments (black) and is lined by a single layer of endothelial cells (which cannot be seen). Further up the blood vessel, the lesion has developed to a more advanced stage, with accumulation of chondrocyte-like cells believed to be involved in calcification of the lesion (middle). Even further up the blood vessel, the lesion shows signs of a necrotic core (caused by dead and dying macrophages), calcification, accumulation of cholesterol in structures called cholesterol clefts, and bleeding in the lesion (intraplaque hemorrhage). Smooth muscle cells have started to cover the macrophage-rich part of the lesion and formed a fibrous cap (right). These advanced atherosclerotic lesions are believed to contribute to cardiovascular events, such as heart attack and stroke. The Program Project focuses on identifying which processes are accelerated by diabetes and the causative factors. Images courtesy of the laboratory of Karin Bornfeldt, PhD.×

Learn more about cardiovascular complications of diabetes from the American Diabetes Association.

 

The Program consists of four different projects and three core units.

Project 1: Role of Serum Amyloid A in Diabetic Vascular Disease – Alan Chait, MD, Project Leader

This project investigates the role of the inflammatory protein serum amyloid A in macrovascular complications of diabetes. Serum amyloid A might contribute to macrovascular complications by promoting retention of cholesterol in the artery wall.

  • Subramanian S, Han CY, Chiba T, McMillen TS, Wang SA, Haw A 3rd, Kirk EA, O’Brien KD, Chait A:  Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese LDL receptor-deficient mice.  Arterioscler Thromb Vasc Biol 28:685-691, 2008.  PMCID: PMC2767166 (Project 1 and Core B)

    Mazzone T, Chait A, Plutzky J:  Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies.  Lancet 371: 1800-1809, 2008.  PMCID:  PMC2774464 (Project 1)

    Chait A, Bornfeldt KE:  Diabetes and atherosclerosis:  Is there a role for hyperglycemia?  J Lipid Res 50 Suppl:S335-9, 2009.  PMCID:  PMC2674740 (Projects 1 and 2)

    Chiba T, Han CY, Vaisar T, Shimokado K, Kargi A, Chen MS, Wang S, McDonald TO, O’Brien KD, Heinecke, JW, Chait A:  Serum amyloid A3 does not contribute directly to increased SAA levels in HDL of obese mice. J Lipid Res 50:1353-1362, 2009.  PMCID: PMC2694334 (Projects 1 and 4, and Cores B and C)

    Hoofnagle A, Vaisar T, Mitra P, Chait A:  HDL lipids and insulin resistance.  Current Diabetes Reports 10:78-86, 2010.  (Review) (Project 1 and Core C)

    Schauer I, Knaub LA, Watson PA, Gliwa C, Lewis K, Chait A, Gunter J, McDonald TO, O’Brien KD, Reusch JEB:  CREB downregulation in vascular disease:  a common response to cardiovascular risk.  Arterioscler Thromb Vasc Biol 30:733-741, 2010.  PMCID:  PMC2841720 (Project 1 and Core B)

    Chait A, Montes VN:  Apolipoproteins and diabetic retinopathy.  Diabetes Care 34:529-531, 2011.  PMCID: PMC3024382 (Project 1)

    Han CY, Kargi AY, Omer M, Chan CK, Wabitsch M, O’Brien KD, Wight TN, Chait A:  Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes:  Dissociation of adipocyte hypertrophy from inflammation. Diabetes 59:386-396, 2011.  PMCID: PMC2809975 (Project 1 and Core B)

    Chiba T, Chang MY, Wang S, Wight TN, McMillen TS, Oram JF, Vaisar T, Heinecke JW, De Beer FC, De Beer MC, Chait A:  Serum amyloid A facilitates the binding of high-density lipoprotein from mice injected with lipopolysaccharide to vascular proteoglycans.  Arterioscler Thromb Vasc Biol 31:1326-1332, 2011.  PMCID: PMC3129975 (Project 1, 3 and 4, and Cores B and C)

    Yoon J, Subramanian S, Ding Y, Wang S, Goodspeed L, Sullivan B, Kim J, O’Brien KD, Chait A: Chronic insulin therapy reduces adipose tissue macrophage content in LDL-receptor-deficient mice.  Diabetologia 54:1252-1260, 2011.  PMCID: PMC3246423 (Project 1 and Core B)

    Handa P, Tateya S, Rizzo NO, Cheng AM, Morgan-Stevenson V, Han CY, Clowes AW, Daum G, O’Brien KD, Schwartz MW, Chait A, Kim F:  Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding. Arterioscler Thromb Vasc Biol 31:2827-2835, 2011.  PMCID:  PMC3342311 (Project 1 and Core B)

    Subramanian S, Goodspeed L, Wang S, Kim J, Zeng L, Ioannou GN, Haigh WG, Yeh MM, Kowdley KV, O’Brien KD, Pennathur S, Chait A:  Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice.  J Lipid Res 52:1626-1635, 2011.  PMCID: PMC3151683 (Project 1 and Core B)

    Cheng AM, Handa P, Tateya S, Schwartz J, Tang C, Mitra P, Oram JF, Chait A, Kim F.  Apolipoprotein A-I attenuates palmitate-mediated NF-kB activation by reducing toll-like receptor-4 recruitment into lipid rafts.  PloS One 7:e33917, 2012.  PMCID:  PMC3316516 (Projects 1 and 3)

    Kanter JE, Kramer F, Barnhart S, Averill MM, Vivekanandan-Giri A, Vickery T, Li LO, Becker L, Yuan W, Chait A, Braun KR, Potter-Perigo S, Sanda S, Wight TN, Pennathur S, Serhan CN, Heinecke JW, Coleman RA, Bornfeldt KE:  Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1.  Proc Natl Acad Sci USA 109:E715-24, 2012.  PMCID:  PMC3311324 (Projects 1, 2 and 4, Cores B and C)

    Chang MY, Chan CK, Braun KR, Green PS, O’Brien KD, Chait A, Day AJ, Wight TN:  Monocyte to macrophage differentiation:  Synthesis and secretion of a complex extracellular matrix.  J Biol Chem 287:14122-14135, 2012.  PMCID:  PMC3340194 (Project 1 and Core B)

    Subramanian S, Chait A:  Hypertriglyceridemia secondary to obesity and diabetes.  Biochim Biophys Acta 1821:819-825, 2012.  (Review) (Project 1)

    Han CY, Umemoto T, Omer M, den Hartigh LJ, Chiba T, LeBoeuf R, Buller CL, Sweet IR, Pennathur S, Abel ED, Chait A: NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes. J Biol Chem 287:10379-10393, 2012.  PMCID:  PMC3322984 (Project 1 and Core B)

    Ding Y, Subramanian S, Montes V, Goodspeed L, Wang S, Han CY, Sta Teresa III A, Kim J, O’Brien K, Chait A: Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 32:1596-1604, 2012.  PMCID: PMC3748807  (Project 1 and Core B)

    Umemoto T, Subramanian S, Ding Y, Goodspeed L, Wang S, Han CY, Sta Teresa A, Kim J, O’Brien KD, Chait A: Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation. J Lipid Res 53:2380-2389, 2012.  PMCID:  PMC3466006 (Project 1 and Core B)

    Lee WJ, Chait A, Kim F:  P-selectin glycoprotein ligand-1:  A cellular link between perivascular adipose inflammation and endothelial dysfunction.  Diabetes 61:3070-3071, 2012.  PMCID:  PMC3501877 (Project 1)

    Umemoto T, Han CY, Mitra P, Averill MM, Tang C, Goodspeed L, Omer MA, Subramanian S, Wang S, Den Hartigh LJ, Wei H, Kim EJ, Kim J, O’Brien KD, Chait A:  Apolipoprotein A-I and high-density lipoprtoein have anti-inflammatory effects on adipocytes via cholesterol transporters:  ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.  Circ Res 112:1345-1354, 2013.  PMCID:  PMC3767575 (Projects 1 and 3, Core B)

    Tateya S, Rizzo-DeLeon N, Handa P, Cheng AM, Morgan-Stevenson V, Ogimoto K, Kanter JE, Bornfeldt KE, Daum G, Clowes AW, Chait A, Kim F:  VASP increases hepatic fatty acid oxidation by activating AMPK in mice. Diabetes 62:1913-1922, 2013. PMCID:  PMC3661609 (Projects 1 and 2, Core B)

    Montes VN, Turner MS, Subramanian S, Ding Y, Hayden-Ledbetter M, Slater S, Goodspeed L, Wang S, Omer M, den Hartigh LJ, Averill MM, O’Brien KD, Ledbetter J, Chait A:  T cell activation inhibitors reduce CD8+ T cell and pro-inflammatory macrophage accumulation in adipose tissue of obese mice.  PLoS One 8:e67709, 2013.  PMCID:  PMC3699637 (Project 1 and Core B)

    Subramanian S, Turner M, Ding Y, Goodspeed L, Wang SA, Buckner J, O’Brien KD, Getz G, Reardon C, Chait A: Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. J Lipid Res 54:2831-2841, 2013. PMCID:  PMC3770095 (Projects 1 and 3, and Core B)

    den Hartigh LJ, Han CY, Wang S, Omer M, Chait A:  10E,12Z-conjugated linoleic acid impairs adipocyte triglyceride storage by enhancing fatty acid oxidation, lipolysis, and mitochondrial reactive oxygen species. J Lipid Res 54:2964-2978, 2013. PMCID:  PMC3793601 (Project 1)

    Wei H, Averill MM, McMillen TS, Dastvan F, Mitra P, Subramanian S, Tang C, Chait A, LeBoeuf RC:  Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice.  Nutr Diabetes 4:e108, 2014.  PMCID:  PMC3940828 (Projects 1 and 3, and Core B)

     

Project 2: Acyl-CoAs and Lesion Initiation in Diabetes – Karin E. Bornfeldt, PhD, Project Leader

This project tests the idea that effects of diabetes on inflammation and formation of atherosclerotic lesions is dependent on the formation of fatty acyl-CoAs in endothelial cells and macrophages.

  • Kanter JE, Averill MM, LeBoeuf RC, Bornfeldt KE:  Diabetes-accelerated atherosclerosis and inflammation. Circ Res 103:e116-117, 2008. PMCID: PMC2645267 (Project 2 and Core B)

    Chait A, Bornfeldt KE:  Diabetes and atherosclerosis: is there a role for hyperglycemia? J Lipid Res 50 Suppl:S335-339, 2009. PMCID: PMC2674740 (Projects 1 and 2)

    Averill MM, Bornfeldt KE:  Lipids versus glucose in inflammation and the pathogenesis of macrovascular disease in diabetes. Curr Diab Rep 9:18-25, 2009. PMCID: PMC3148110 (Project 2)

    Li S, Sun Y, Liang CP, Thorp EB, Han S, Jehle AW, Saraswathi V, Pridgen B, Kanter JE, Li R, Welch CL, Hasty AH, Bornfeldt KE, Breslow JL, Tabas I, Tall AR:  Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet. Circ Res 105:1072-1082, 2009. PMCID: PMC2818555 (Project 2)

    Raines EW, Bornfeldt KE:Integrin alpha(7)beta(1) COMPels smooth muscle cells to maintain their quiescence. Circ Res 106:427-429, 2010. PMCID: PMC2847492 (Project 2)

    Tang C, Kanter JE, Bornfeldt KE, LeBoeuf RC, Oram JF:  Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys. J Lipid Res 51:1719-1728, 2010. PMCID: PMC2882721 (Projects 2 and 3, and Core B)

    Golej DL, Askari B, Kramer F, Barnhart S, Vivekanandan-Giri A, Pennathur S, Bornfeldt KE:  Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells. J Lipid Res 52:782-793, 2011. PMCID: PMC3053208 (Project 2)

    Averill MM, Barnhart S, Becker L, Li X, Heinecke JW, LeBoeuf RC, Hamerman JA, Sorg C, Kerkhoff C, Bornfeldt KE:  S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells: implications for atherosclerosis and adipose tissue inflammation. Circulation 123:1216-1226, 2011. PMCID: PMC3072335 (Projects 2, 3 and 4, and Cores B and C)

    Bornfeldt KE:  Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab 14:575-585, 2011. PMCID: PMC3217209 (Project 2)

    Nishizawa T, Bornfeldt KE:  Diabetic vascular disease and the potential role of macrophage glucose metabolism. Ann Med 44:555-563, 2012. PMCID: PMC3430835 (Project 2)

    Kanter JE, Tang C, Oram JF, Bornfeldt KE:  Acyl-CoA synthetase 1 is required for oleate and linoleate mediated inhibition of cholesterol efflux through ATPbinding cassette transporter A1 in macrophages. Biochim Biophys Acta 1821:358-364, 2012. PMCID: PMC3266440 (Projects 2 and 3)

    Averill MM, Kerkhoff C, Bornfeldt KE:  S100A8 and S100A9 in cardiovascular biology and disease. Arterioscler Thromb Vasc Biol 32:223-229, 2012. PMCID: PMC3262097 (Project 2)

    Kanter JE, Kramer F, Barnhart S, Averill MM, Vivekanandan-Giri A, Vickery T, Li LO, Becker L, Yuan W, Chait A, Braun KR, Potter-Perigo S, Sanda S, Wight TN, Pennathur S, Serhan CN, Heinecke JW, Coleman RA, Bornfeldt KE:  Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis via acyl-CoA synthetase 1. Proc Natl Acad Sci USA 109:E715-724, 2012. PMCID: PMC3311324 (Projects 1, 2 and 4, Cores B and C)

    Becker L, Liu NC, Averill MM, Yuan W, Pamir N, Peng Y, Irwin AD, Fu X, Bornfeldt KE, Heinecke JW:  Unique proteomic signatures distinguish macrophages and dendritic cells. PLoS One 7:e33297, 2012. PMCID: PMC3299764 (Projects 2 and 4, Cores B and C)

    Pathare PP, Lin A, Bornfeldt KE, Taubert S, Van Gilst MR:  Coordinate regulation of lipid metabolism by novel nuclear receptor partnerships. PLoS Genet 8:e1002645, 2012. PMCID: PMC3325191 (Project 2)

    Kerkhoff C, Voss A, Scholzen TE, Averill MM, Zänker KS, Bornfeldt KE:  Novel insights into the role of S100A8/A9 in skin biology. Exp Dermatol 21:822-826, 2012. PMCID: PMC3498607 (Project 2)

    Kanter JE, Bornfeldt KE:  Inflammation and diabetes-accelerated atherosclerosis: myeloid cell mediators. Trends Endocrinol Metab 24:137-144, 2013.  PMCID:  PMC3578033 (Project 2)

    Rubinow KB, Bornfeldt KE: Microvascular management of systemic insulin sensitivity.  Circ Res 111:951-953, 2012.  PMCID:  PMC3488957 (Project 2)

    Li X, Gonzalez O, Shen X, Barnhart S, Kramer F, Kanter JE, Vivekanandan-Giri A, Tsuchiya K, Handa P, Pennathur S, Kim F, Coleman RA, Schaffer JE, Bornfeldt KE:  Endothelial acyl-CoA synthetase 1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment.  Arterioscler Thromb Vasc Biol 33:232-240, 2013.  PMCID: PMC3553857 (Project 2 and Core B)

    Tateya S, Rizzo-DeLeon N, Handa P, Cheng AM, Morgan-Stevenson V, Ogimoto K, Kanter JE, Bornfeldt KE, Daum G, Clowes AW, Chait A, Kim F:  VASP increases hepatic fatty acid oxidation by activating AMPK in mice. Diabetes 62:1913-1922, 2013. PMCID:  PMC3661609 (Projects 1 and 2, Core B)

    Rubinow KB, Wall VZ, Nelson J, Mar D, Bomsztyk K, Askari B, Lai MA, Smith KD, Han MS, Vivekanandan-Giri A, Pennathur S, Albert CJ, Ford DA, Davis RJ, Bornfeldt KE:  Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages.  J Biol Chem 288:9957-9970, 2013.  PMCID: PMC3617295 (Project 2)

    Kanter JE, Bornfeldt KE:  Evidence stacks up that endothelial insulin resistance is a culprit in atherosclerosis.  Circ Res 113:352-354, 2013.  PMCID:  PMC3841007 (Project 2)

    Goldberg IJ, Bornfeldt KE:  Lipids and the endothelium:  Bidirectional interactions. Curr Atheroscler Rep. 15:365, 2013.  PMCID:  PMC3825167 (Project 2)

    Bornfeldt, KE:  2013 Russell Ross Memorial Lecture in Vascular Biology:  Cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis.  Arterioscler Thromb Vasc Biol 34:705-l714, 2014.  PMCID:  PMC3967130 (Project 2)

    Nishizawa T, Kanter JE, Kramer F, Barnhart S, Shen X, Vivekanandan-Giri A, Wall VZ, Kowitz J, Devaraj S, O’Brien KD, Pennathur S, Tang J, Miyaoka RS, Raines EW, Bornfeldt KE. Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep. 7:356-65, 2014.PMC Journal – In Process. (Project 2 and Core B)

    Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, Dragoljevic D, Hong ES, Abdel-Latif A, Smyth SS, Choi SH, Korner J, Bornfeldt KE, Fisher EA, Dixit VD, Tall AR, Goldberg IJ, Murphy AJ: Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.  Cell Metab 19:821-835, 2014.  PMC Journal – In Process. (Project 2)

    Taborsky GJ Jr, Mei Q, Bornfeldt KE, Hackney DJ, Mundinger TO: The p75 neurotrophin receptor is required for the major loss of sympathetic nerves from islets under autoimmune attack. Diabetes 2014 Mar 7. [Epub ahead of print]. PMC Journal – In Process (Project 2)

    Lee JT, Pamir N, Liu NC, Kirk EA, Averill MM, Becker L, Larson I, Hagman DK, Foster-Schubert KE, van Yserloo B, Bornfeldt KE, LeBoeuf RC, Kratz M, Heinecke JW: Macrophage metalloelastase (Mmp12) regulates adipose tissue expansion, insulin sensitivity, and the expression of inducible nitric oxide synthase. In press. (Projects 2, 3 and 4, and Cores B and C)

     

Project 3: Reverse Cholesterol Transport in Diabetes – John F. Oram, PhD, Godfrey Getz, MD, PhD, Project Leaders

This project investigates the concept that diabetes results in increased accumulation of cholesterol in macrophages by negatively modifying a cholesterol transport protein (ABCA1), and that agents that stimulate cholesterol efflux might be able to prevent atherosclerosis associated with diabetes.

  • Vaughan AM, Tang C, Oram JF: ABCA1 mutants reveal an interdependency between lipid export function, apoA-I binding activity, and Janus kinase 2 activation.  J Lipid Res 50:285-292, 2009.  PMCID:  PMC2636916 (Project 3)

    Tang C, Liu Y, Kessler PS, Vaughan AM, Oram JF:  The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor.  J Biol Chem 284:32336-32343, 2009.  PMCID:  PMC2781648 (Project 3)

    Tang C, Oram JF:  The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes.  Biochim Biophys Acta 179:563-572, 2009.  (Review) (Project 3)

    Becker L, Gharib SA, Irwin AD, Wijsman E, Vaisar T, Oram JF, Heinecke JW:  A macrophage sterol-responsive network linked to atherogenesis.  Cell Metab 11:125-135, 2010.  PMCID:  PMC2893224 (Projects 3 and 4, and Cores B and C)

    Shao B, Oda MN, Oram JF, Heinecke JW:  Myeloperoxidase:  An oxidative pathway for generating dysfunctional high-density lipoprotein.  Chem Res Toxicol 23:447-454, 2010. PMCID: PMC2838938 (Projects 3 and 4, and Core C)

    Shao B, Pennathur S, Pagani I, Oda MN, Witztum JL, Oram JF, Heinecke JW:  Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway.  J Biol Chem 285:18473-18484, 2010.  PMC2881773 (Projects 3 and 4, Core C)

    Suzuki M, Pritchard DK, Becker L, Hoofnagle AN, Tanimura N, Bammler TK, Beyer RP, Bumgarner R, Vaisar T, de Beer MC, de Beer FC, Miyake K, Oram JF, Heinecke JW:  High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide.  Circulation 122:1919-1927, 2010.  PMC2988582 (Projects 3 and 4, and Cores B and C)

    Tang C, Kanter JE, Bornfeldt KE, LeBoeuf RC, Oram JF:  Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys.  J Lipid Res 51:1849-1858, 2010.  PMCID:  PMC2882721 (Projects 2 and 3, and Core B)

    Shao B, Tang C, Heinecke JW, Oram JF:  Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export.  J Lipid Res 51:1919-1928, 2010.  PMCID:  PMC2882738 (Projects 3 and 4, Core C)

    Averill MM, Barnhart S, Becker L, Li X, Heinecke JW, LeBoeuf RC, Hamerman JA, Sorg C, Kerkhoff C, Bornfeldt KE:  S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells:  Implications for atherosclerosis and adipose tissue inflammation.  Circulation 123:1216-1226, 2011.  PMCID:  PMC3072335 (Projects 2, 3 and 4, and Cores B and C)

    Liu Y and Tang C:  Regulation of ABCA1 functions by signaling pathways.  Biochim Biophys Acta 1821:522-529. 2011.  PMCID:  PMC3243790 (Project 3)

    Chiba T, Chang MY, Wang S, Wight TN, McMillen TS, Oram JF, Vaisar T, Heinecke JW, De Beer FC, De Beer MC, Chait A:  Serum amyloid A facilitates the binding of high-density lipoprotein from mice injected with lipopolysaccharide to vascular proteoglycans.  Arterioscler Thromb Vasc Biol 31:1326-1332, 2011.  PMCID: PMC3129975 (Projects 1, 3 and 4, and Cores B and C)

    Paik J, Fierce Y, Mai PO, Phelps SR, McDonald T, Treuting P, Drivdahl R, Brabb T, LeBoeuf R, O’Brien KD, Maggio-Price L:  Murine norovirus increased atherosclerotic lesion size and inflammation in Ldlr-/- mice.  Comp Med 61:330-338, 2011.  PMCID:  PMC3155399 (Project 3 and Core B)

    Kanter JE, Tang C, Oram JF, Bornfeldt KE:  Acyl-CoA synthetase 1 is required for oleate and linoleate mediated inhibition of cholesterol efflux through ATP-binding cassette transporter A1 in macrophages.  Biochim Biophys Acta 1821:358-364, 2012.  PMCID:  PMC3266440 (Projects 2 and 3)

    Cheng AM, Handa P, Tateya S, Schwartz J, Tang C, Mitra P, Oram JF, Chait A, Kim F.  Apolipoprotein A-I attenuates palmitate-mediated NF-kB activation by reducing toll-like receptor-4 recruitment into lipid rafts.  PloS One 7:e33917, 2012.  PMCID:  PMC3316516 (Projects 1 and 3)

    Edgel KA, McMillen TS, Wei H, Pamir N, Houston BA, Caldwell MT, Mai PO, Oram JF, Tang C, LeBoeuf RC:  Obesity and weight loss result in increased adipose tissue ABCG1 expression in db/db Mice.  Biochim Biophys Acta 1821:425-434, 2012.  PMCID:  PMC3293702 (Project 3 and Core B)

    Suzuki M, Becker L, Pritchard DK, Gharib SA, Wijsman EM, Bammler TK, Beyer RP, Vaisar T, Oram JF, Heinecke JW:  Cholesterol accumulation regulates expression of macrophage proteins implicated in proteolysis and complement activation.  Arterioscler Thromb Vasc Biol 32:2910-2918, 2012.  PMCID:  PMC3501207 (Projects 3 and 4, and Cores B and C)

    Rubinow KB, Vaisar T, Tang C, Matsumoto AM, Heinecke JW, Page ST: Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J Lipid Res 53:1376-1383, 2012.  PMCID: PMC3371249 (Projects 3 and 4, and Core C)

    Page ST, Krauss RM, Gross C, Ishida B, Heinecke JW, Tang C, Amory JK, Schaefer PM, Cox CJ, Kane J, Purnell JQ, Weinstein RL, Vaisar T: Impact of mifepristone, a glucocorticoid/progesterone antagonist, on HDL cholesterol, HDL particle concentration, and HDL function. J Clin Endocrinol Metab 97:1598-1605, 2012. PMCID: PMC3339893 (Projects 3 and 4, and Core C)

    Rubinow KB, Tang C, Hoofnagle AN, Snyder CN, Amory JK, Heinecke JW, Page ST: Acute sex steroid withdrawal increases cholesterol efflux capacity and HDL-associated clusterin in men. Steroids 77:454-460, 2012. PMCID: PMC3304018 (Projects 3 and 4, and Core C)

    Subramanian S, Turner M, Ding Y, Goodspeed L, Wang SA, Buckner J, O’Brien KD, Getz G, Reardon C, Chait A: Increased levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. J Lipid Res 54:2831-2841, 2013. PMCID:  PMC3770095 (Projects 1 and 3, and Core B)

    McMillen TS, Minami E, LeBoeuf RC:  Atherosclerosis and cardiac function assessment in low-density lipoprotein receptor-deficient mice undergoing body weight cycling.  Nutr Diabetes 3:e79, 2013.  PMCID: PMC2697407. (Project 3 and Core B)

    Umemoto T, Han CY, Mitra P, Averill MM, Tang C, Goodspeed L, Omer MA, Subramanian S, Wang S, Den Hartigh LJ, Wei H, Kim EJ, Kim J, O’Brien KD, Chait A:  Apolipoprotein A-I and high-density lipoprtoein have anti-inflammatory effects on adipocytes via cholesterol transporters:  ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.  Circ Res 112:1345-1354, 2013.  PMCID:  PMC3767575 (Projects 1 and 3, Core B)

    Vivekanandan-Giri A, Slocum JL, Byun J, Tang C, Sands RL, Gillespie BW, Heinecke JW, Saran R, Kaplan MJ, Pennathur S:  High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis. Ann Rheum Dis 72:1725-1731, 2013.  PMID:  23313808 (Projects 3 and 4, Core C)

    Wei H, Averill MM, McMillen TS, Dastvan F, Mitra P, Subramanian S, Tang C, Chait A, LeBoeuf RC:  Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice.  Nutr Diabetes 4:e108, 2014.  PMCID:  PMC3940828 (Projects 1 and 3, and Core B)

    Lee JT, Pamir N, Liu NC, Kirk EA, Averill MM, Becker L, Larson I, Hagman DK, Foster-Schubert KE, van Yserloo B, Bornfeldt KE, LeBoeuf RC, Kratz M, Heinecke JW: Macrophage metalloelastase (Mmp12) regulates adipose tissue expansion, insulin sensitivity, and the expression of inducible nitric oxide synthase. In press. (Projects 2, 3 and 4, and Cores B and C)

     

Project 4: Molecular Mechanisms of Atherogenesis in Diabetes – Jay W. Heinecke, MD, Project Leader

This project is centered on understanding molecular mechanisms of tissue injury caused by oxidation in diabetic macrovascular complications.

  • Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC, Schwartz MW, Niswender KD: Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. Am J Physiol Endocrinol Metab 296:E1003-E1012, 2009. PMCID: PMC2681305 (Project 4)

    Chiba T, Han CY, Vaisar T, Shimokado K, Kargi A, Chen MH, Wang S, McDonald TO, O’Brien KD, Heinecke JW, Chait A: Serum amyloid A3 does not contribute to circulating SAA levels. J Lipid Res 50:1353-1362, 2009. PMCID: PMC2694334 (Projects 1 and 4, and Cores B and C)

    Shao B, Heinecke JW: HDL, lipid peroxidation, and atherosclerosis. J Lipid Res 50:599-601, 2009. PMCID: PMC2656652 (Project 4 and Core C)

    Hoofnagle AF, Heinecke JW: Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structures, and functions of lipoproteins. J Lipid Res 50:1967-1975, 2009. PMCID: PMC2739765 (Project 4 and Core C)

    Shao B, Oda MN, Oram JF, Heinecke JW: Myeloperoxidase: An oxidative pathway for generating dysfunctional high-density lipoprotein. Chem Res Toxicol 23:447-454, 2010. PMCID: PMC2838938 (Projects 3 and 4, and Core C)

    Shao B, Tang C, Heinecke JW, Oram JF: Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export. J Lipid Res 1849-1858, 2010. PMCID: PMC2882738 (Projects 3 and 4, and Core C)

    Heinecke JW: The Protein Cargo of HDL: Implications for vascular wall biology and therapeutics. J Clin Lipidol 4:371-375, 2010. PMCID: PMC2959168 (Project 4)

    Cheung MC, Vaisar T, Han X, Heinecke JW, Albers JJ: Phospholipid transfer protein in human plasma associates with proteins linked to immunity and inflammation. Biochemistry 49:7314-7322 2010. PMCID: PMC2930196 (Project 4 and Core C)

    Cavigiolio G, Geier EG, Shao B, Heinecke JW, Oda MN: Exchange of apolipoprotein A-I between lipid-associated and lipid-free states: A potential target for oxidative generation of dysfunctional high density lipoproteins. J Biol Chem 285:18847-18857, 2010. PMCID: PMC2881807 (Project 4 and Core C)

    Shao B, Pennathur S, Pagani I, Oda MN, Witztum JL, Oram JF, Heinecke JW: Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway. J Biol Chem 285:18473-18484, 2010. PMCID: PMC2881773 (Projects 3 and 4, and Core C)

    Becker L, Gharib SA, Irwin AD, Wijsman E, Vaisar T, Oram JF, Heinecke JW: A macrophage sterol-responsive network linked to atherogenesis. Cell Metab 11:125-135, 2010. PMCID: PMC2893224 (Projects 3 and 4, and Core C)

    Hoofnagle AN, Wu M, Gosmanova AK, Becker JO, Wijsman EM, Brunzell JD, Kahn SE, Knopp RH, Lyons TJ, Heinecke JW: Low clusterin levels in high density lipoprotein associate with insulin resistance and obesity. Arterioscler Thromb Vasc Biol 30:2528-2534, 2010. PMCID: PMC2988100 (Project 4 and Core C)

    Suzuki M, Pritchard DK, Becker L, Hoofnagle AN, Tanimura N, Bammler TK, Beyer RP, Bumgarner R, Vaisar T, de Beer MC, de Beer FC, Miyake K, Oram JF, Heinecke JW: High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide. Circulation 122:1919-1927, 2010. PMCID: PMC2988582 (Projects 3 and 4, and Cores B and C)

    Averill MM, Barnhart S, Becker L, Li X, Heinecke JW, LeBoeuf RC, Hamerman JA, Sorg C, Kerkhoff C, Bornfeldt KE: S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells: Implications for Atherosclerosis and Adipose Tissue Inflammation. Circulation 123:1216-1226, 2011. PMCID: PMC3072335 (Projects 2, 3 and 4, and Core B and C)

    Heinecke, JW: HDL and cardiovascular disease risk: Time for a new approach? N Engl J Med 364:170-171, 2011. (Review) (Project 4)

    Chiba T, Chang MY, Wang S, Wight TN, McMillen TS, Oram JF, Vaisar T, Heinecke JW, De Beer FC, De Beer MC, Chait A: Serum amyloid A facilitates the binding of high-density lipoprotein from mice injected with lipopolysaccharide to vascular proteoglycans. Arterioscler Thromb Vasc Biol 31:1326-1332, 2011. PMCID: PMC3129975 (Projects 1, 3 and 4, and Cores B and C)

    Shao B, Heinecke JW: Impact of HDL oxidation by the myeloperoxidase system on sterol efflux by the ABCA1 pathway. J Proteomics 74:2289-2299, 2011. PMCID: PMC3156866 (Project 4 and Core C)

    Kanter JE, Kramer F, Barnhart S, Averill MM, Vivekanandan-Giri A, Vickery T, Li LO, Becker L, Yuan W, Chait A, Braun KR, Potter-Perigo S, Sanda S, Wight TN, Pennathur S, Serhan CN, Heinecke JW, Coleman RA, Bornfeldt KE: Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA Synthetase 1. Proc Natl Acad Sci USA 109:E715-724, 2012. PMCID: PMC3311324 (Projects 1, 2 and 4, Cores B and C)

    Shao B, Pennathur S, Heinecke JW: Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions. J Biol Chem 287:6375-6386, 2012. PMCID: PMC3307260 (Project 4 and Core C)

    Becker L, Liu NC, Averill MM, Yuan W, Pamir N, Peng Y, Irwin AD, Fu X, Bornfeldt KE, Heinecke JW: Unique proteomic signatures distinguish macrophages and dendritic cells. PLoS One 7:e33297, 2012. PMCID: PMC3299764 (Projects 2 and 4, Cores B and C)

    Suzuki M, Becker L, Pritchard DK, Gharib SA, Wijsman EM, Bammler TK, Beyer RP, Vaisar T, Oram JF, Heinecke JW: Cholesterol accumulation regulates expression of macrophage proteins implicated in proteolysis and complement activation. Arterioscler Thromb Vasc Biol 32:2910-2918, 2012. PMCID: PMC3501207 (Projects 3 and 4, and Cores B and C)

    Rubinow KB, Vaisar T, Tang C, Matsumoto AM, Heinecke JW, Page ST: Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J Lipid Res 53:1376-1383, 2012.  PMCID: PMC3371249 (Projects 3 and 4, and Core C)

    Page ST, Krauss RM, Gross C, Ishida B, Heinecke JW, Tang C, Amory JK, Schaefer PM, Cox CJ, Kane J, Purnell JQ, Weinstein RL, Vaisar T: Impact of mifepristone, a glucocorticoid/progesterone antagonist, on HDL cholesterol, HDL particle concentration, and HDL function. J Clin Endocrinol Metab 97:1598-1605, 2012. PMCID: PMC3339893 (Projects 3 and 4, and Core C)

    Heinecke JW:  HDL’s protein cargo:  Friend or foe in cardioprotection? Circulation 127:868-869, 2013. (Editorial) (Project 4 and Core C)

    Vivekanandan-Giri A, Slocum JL, Byun J, Tang C, Sands RL, Gillespie BW, Heinecke JW, Saran R, Kaplan MJ, Pennathur S:  High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis. Ann Rheum Dis 72:1725-1731, 2013.  PMID:  23313808 (Projects 3 and 4, Core C)

    Lee JT, Pamir N, Liu NC, Kirk EA, Averill MM, Becker L, Larson I, Hagman DK, Foster-Schubert KE, van Yserloo B, Bornfeldt KE, LeBoeuf RC, Kratz M, Heinecke JW: Macrophage metalloelastase (Mmp12) regulates adipose tissue expansion, insulin sensitivity, and the expression of inducible nitric oxide synthase. In press. (Projects 2, 3 and 4, and Cores B and C)

     

Core A: Administrative Core – Karin E. Bornfeldt, PhD, Core Director, Alan Chait, MD, Core Co-Director

The Administrative Core is responsible for the overall management of and direction of the Program.

Core B: Mouse and Tissue Core – Kevin D, O’Brien, MD, and Renee L. LeBoeuf, PhD, Core Directors

This Core provides services related to analysis of atherosclerosis.

  • Subramanian S, Han CY, Chiba T, McMillen TS, Wang SA, Haw A 3rd, Kirk EA, O’Brien KD, Chait A:  Dietary cholesterol worsens adipose tissue macrophage accumulation and atherosclerosis in obese, insulin resistant LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 28:685-91, 2008.  PMCID:  PMC2767166 (Project 1 and Core B)

    Kanter JE, Averill MM, LeBoeuf RC, Bornfeldt KE:  Diabetes-accelerated atherosclerosis and inflammation. Circ Res 103:e116-117, 2008. PMCID: PMC2645267 (Project 2 and Core B)

    Chiba T, Han C-Y, Vaisar T, Shimokado K, Kargi A, Chen M-H, Wang S, McDonald TO, O’Brien KD, Heinecke JW, Chait A:  Serum amyloid A3 does not contribute directly to increased SAA levels in HDL of obese mice. J Lipid Res 50:1353-1362, 2009.  PMCID:  PMC2694334 (Projects 1 and 4, and Cores B and C)

    Han CY, Kargi A, Omer M, Chan CK, O’Brien KD, Wight TN, Chait A:  Differential effect of saturated and unsaturated free fatty acids on the generation of monocyte adhesion and chemotactic factors by adipocytes:  Dissociation of adipocyte hypertrophy from inflammation.  Diabetes 59:386-396, 2010.  PMCID:  PMC2809975 (Project 1 and Core B)

    Becker L, Gharib SA, Irwin AD, Wijsman E, Vaisar T, Oram JF, Heinecke JW:  A macrophage sterol-responsive network linked to atherogenesis.  Cell Metab 11:125-135, 2010.  PMCID:  PMC2893224 (Projects 3 and 4, and Cores B and C)

    Suzuki M, Pritchard DK, Becker L, Hoofnagle AN, Tanimura N, Bammler TK, Beyer RP, Bumgarner R, Vaisar T, de Beer MC, de Beer FC, Miyake K, Oram JF, Heinecke JW: High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide. Circulation 122:1919-1927, 2010. PMCID: PMC2988582 (Projects 3 and 4, and Cores B and C)

    Tang C, Kanter JE, Bornfeldt KE, LeBoeuf RC, Oram JF:  Diabetes reduced the cholesterol exporter ABCA1 in mouse macrophages and kidneys.  J Lipid Res 51:1719-1728, 2010.  PMCID:  PMC2882721 (Projects 2 and 3, and Core B)

    Schauer I, Knaub LA, Watson PA, Gliwa C, Lewis K, Chait A, Gunter J, McDonald TO, O’Brien KD, Reusch JEB:  CREB downregulation in vascular disease:  a common response to cardiovascular risk.  Arterioscler Thromb Vasc Biol 30:733-741, 2010.  PMCID:  PMC2841720 (Project 1 and Core B)

    Yoon J, Subramanian S, Ding Y, Wang S, Goodspeed L, Sullivan B, O’Brien KD, Chait, A:  Chronic insulin therapy reduces adipose tissue macrophage content but does not improve systemic inflammation in LDL receptor-deficient mice.  Diabetologia 54:1252-1260, 2011.  PMCID:  PMC3246423 (Project 1 and Core B)

    Chiba T, Chang MY, Wang S, Wight TN, McMillen TS, Oram JF, Vaisar T, Heinecke JW, De Beer FC, De Beer MC, Chait A:  Serum amyloid A facilitates the binding of high-density lipoprotein from mice injected with lipopolysaccharide to vascular proteoglycans.  Arterioscler Thromb Vasc Biol 31:1326-1332, 2011.  PMCID: PMC3129975 (Projects 1, 3 and 4, and Cores B and C)

    Paik J, Fierce Y, Mai PO, Phelps SR, McDonald T, Treuting P, Drivdahl R, Brabb T, LeBoeuf R, O’Brien KD, Maggio-Price L:  Murine norovirus increased atherosclerotic lesion size and inflammation in Ldlr-/- mice.  Comp Med 61:330-338, 2011.  PMCID:  PMC3155399 (Project 3 and Core B)

    Subramanian S, Goodspeed L, Wang S, Kim J, Zeng L, Ioannou GN, Haigh WG, Yeh MM, Kowdley KV, O’Brien KD, Pennathur S, Chait A:  Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice.  J Lipid Res 52:1626-1635, 2011.  PMCID: PMC3151683 (Project 1 and Core B)

    Averill MM, Barnhart S, Becker L, Li X, Heinecke JW, LeBoeuf RC, Hamerman JA, Sorg C, Kerkhoff C, Bornfeldt KE:  S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells: implications for atherosclerosis and adipose tissue inflammation. Circulation 123:1216-1226, 2011. PMCID: PMC3072335 (Projects 2, 3 and 4, and Cores B and C)

    Handa P, Tateya S, Rizzo NO, Cheng AM, Morgan-Stevenson V, Han C-Y, Clowes AW, Daum G, O’Brien KD, Schwartz MW, Chait A, Kim F:  Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding.  Arterioscler Thromb Vasc Biol 31:2827-2835, 2011.  PMCID:  PMC3342311 (Project 1 and Core B)

    Suzuki M, Becker L, Pritchard DK, Gharib SA, Wijsman EM, Bammler TK, Beyer RP, Vaisar T, Oram JF, Heinecke JW: Cholesterol accumulation regulates expression of macrophage proteins implicated in proteolysis and complement activation. Arterioscler Thromb Vasc Biol 32:2910-2918, 2012. PMCID: PMC3501207 (Projects 3 and 4, and Cores B and C)

    Chang MY, Chan CK, Braun KR, Green PS, O’Brien KD, Chait A, Day AJ, Wight TN:  Monocyte to macrophage differentiation:  Synthesis and secretion of a complex extracellular matrix.  J Biol Chem 287:14122-14135, 2012.  PMCID:  PMC3340194 (Project 1 and Core B)

    Kanter JE, Kramer F, Barnhart S, Averill MM, Vivekanandan-Giri A, Vickery T, Li LO, Becker L, Yuan W, Chait A, Braun KR, Potter-Perigo S, Sanda S, Wight TN, Pennathur S, Serhan CN, Heinecke JW, Coleman RA, Bornfeldt KE:  Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1.  Proc Natl Acad Sci USA 109:E715-24, 2012.  PMCID:  PMC3311324 (Projects 1, 2 and 4, Cores B and C)

    Han CY, Umemoto T, Omer M, den Hartigh LJ, Chiba T, LeBoeuf R, Buller CL, Sweet IR, Pennathur S, Abel ED, Chait A: NADPH oxidase-derived reactive oxygen species increases expression of monocyte chemotactic factor genes in cultured adipocytes. J Biol Chem 287:10379-10393, 2012.  PMCID:  PMC3322984 (Project 1 and Core B)

    Becker L, Liu NC, Averill MM, Yuan W, Pamir N, Peng Y, Irwin AD, Fu X, Bornfeldt KE, Heinecke JW:  Unique proteomic signatures distinguish macrophages and dendritic cells. PLoS One 7:e33297, 2012. PMCID: PMC3299764 (Projects 2 and 4, Cores B and C)

    Ding Y, Subramanian S, Montes V, Goodspeed L, Wang S, Han CY, Sta Teresa III A, Kim J, O’Brien K, Chait A: Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 32:1596-1604, 2012.  PMCID:  PMC3748807  (Project 1 and Core B)

    Umemoto T, Subramanian S, Ding Y, Goodspeed L, Wang S, Han CY, Sta Teresa A, Kim J, O’Brien KD, Chait A: Inhibition of intestinal cholesterol absorption decreases atherosclerosis but not adipose tissue inflammation. J Lipid Res 53:2380-2389, 2012.  PMCID:  PMC3466006 (Project 1 and Core B)

    Li X, Gonzalez O, Shen X, Barnhart S, Kramer F, Kanter JE, Vivekanandan-Giri A, Tsuchiya K, Handa P, Pennathur S, Kim F, Coleman RA, Schaffer JE, Bornfeldt KE:  Endothelial acyl-CoA synthetase 1 is not required for inflammatory and apoptotic effects of a saturated fatty acid-rich environment.  Arterioscler Thromb Vasc Biol 33:232-240, 2013.  PMCID: PMC3553857 (Project 2 and Core B)

    Edgel KA, McMillen TS, Wei H, Pamir N, Houston BA, Caldwell MT, Mai P-O T, Oram JF, Tang C, LeBoeuf RC:  Obesity and weight loss result in increased adipose tissue ABCG1 expression in db/db mice.  Biochem Biophy Acta 1821:425-434, 2012. PMCID:  PMC3293702 (Project 3 and Core B)

    Tateya S, Rizzo-DeLeon N, Handa P, Cheng AM, Morgan-Stevenson V, Ogimoto K, Kanter JE, Bornfeldt KE, Daum G, Clowes AW, Chait A, Kim F:  VASP increases hepatic fatty acid oxidation by activating AMPK in mice. Diabetes 62:1913-1922, 2013. PMCID:  PMC3661609 (Projects 1 and 2, Core B)

    Umemoto T, Han CY, Mitra P, Averill MM, Tang C, Goodspeed L, Omer MA, Subramanian S, Wang S, Den Hartigh LJ, Wei H, Kim EJ, Kim J, O’Brien KD, Chait A:  Apolipoprotein A-I and high-density lipoprtoein have anti-inflammatory effects on adipocytes via cholesterol transporters:  ATP-binding cassette A-1, ATP-binding cassette G-1, and scavenger receptor B-1.  Circ Res 112:1345-1354, 2013.  PMCID:  PMC3767575 (Projects 1 and 3, Core B)

    Montes VN, Turner MS, Subramanian S, Ding Y, Hayden-Ledbetter M, Slater S, Goodspeed L, Wang S, Omer M, den Hartigh LJ, Averill MM, O’Brien KD, Ledbetter J, Chait A:  T cell activation inhibitors reduce CD8+ T cell and pro-inflammatory macrophage accumulation in adipose tissue of obese mice.  PLoS One 8:e67709, 2013.  PMCID:  PMC3699637 (Project 1 and Core B)

    McMillen TS, Minami E, LeBoeuf RC:  Atherosclerosis and cardiac function assessment in low-density lipoprotein receptor-deficient mice undergoing body weight cycling.  Nutr Diabetes 3:e79, 2013.  PMCID: PMC2697407. (Project 3 and Core B)

    Subramanian S, Turner M, Ding Y, Goodspeed L, Wang SA, Buckner J, O’Brien KD, Getz G, Reardon C, Chait A: Increasied levels of invariant natural killer T lymphocytes worsen metabolic abnormalities and atherosclerosis in obese mice. J Lipid Res 54:2831-2841, 2013. PMCID:  PMC3770095 (Projects 1 and 3, and Core B)

    Nishizawa T, Vivekanandan-Giri A, Kramer F, Handa P, Barnhart S, Kanter JE, Kim F, O’Brien KD, Pennathur S, Raines EW, Bornfeldt KE:  Increased glycolysis is a result rather than a cause of inflammatory activation in macrophages. Cell Rep 7:356-365, 2014.  PMC Journal – In Process (Project 2 and Core B)

    Wei H, Averill MM, McMillen TS, Dastvan F, Mitra P, Subramanian S, Tang C, Chait A, LeBoeuf RC:  Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice.  Nutr Diabetes 4:e108, 2014.  PMCID:  PMC3940828 (Projects 1 and 3, and Core B)

    Lee JT, Pamir N, Liu NC, Kirk EA, Averill MM, Becker L, Larson I, Hagman DK, Foster-Schubert KE, van Yserloo B, Bornfeldt KE, LeBoeuf RC, Kratz M, Heinecke JW: Macrophage metalloelastase (Mmp12) regulates adipose tissue expansion, insulin sensitivity, and the expression of inducible nitric oxide synthase. Endocrinology In press. (Projects 2, 3 and 4, and Cores B and C)

     

Core C: Mass Spectrometry Core – Jay W. Heinecke, MD, and Tomas Vaisar, PhD, Core Directors

This Core provides services in sophisticated mass spectrometry to analyse oxidation of tissues and specific molecules.

  • Chiba T, Han CY, Vaisar T, Shimokado K, Kargi A, Chen MS, Wang S, McDonald TO, O’Brien KD, Heinecke, JW, Chait A:  Serum amyloid A3 does not contribute directly to increased SAA levels in HDL of obese mice. J Lipid Res 50:1353-1362, 2009.  PMCID: PMC2694334 (Projects 1 and 4, and Cores B and C)

    Shao B, Heinecke JW:  HDL, lipid peroxidation, and atherosclerosis.  J Lipid Res 50:599-601, 2009. PMCID: PMC2656652 (Project 4 and Core C)

    Hoofnagle AF, Heinecke JW:  Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structures, and functions of lipoproteins. J Lipid Res 50:1967-1975, 2009. PMCID:  PMC2739765 (Project 4 and Core C)

    Hoofnagle A, Vaisar T, Mitra P, Chait A:  HDL lipids and insulin resistance.  Current Diabetes Reports 10:78-86, 2010.  (Review) (Project 1 and Core C)

    Shao B, Oda MN, Oram JF, Heinecke JW:  Myeloperoxidase:  An oxidative pathway for generating dysfunctional high-density lipoprotein.  Chem Res Toxicol 23:447-454, 2010.  PMCID:  PMC2838938 (Projects 3 and 4, and Core C)

    Shao B, Tang C, Heinecke JW, Oram JF:  Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export.  J Lipid Res 1849-1858, 2010.  PMCID:  PMC2882738 (Projects 3 and 4, and Core C)

    Cheung MC, Vaisar T, Han X, Heinecke JW, Albers JJ:  Phospholipid transfer protein in human plasma associates with proteins linked to immunity and inflammation.  Biochemistry 49:7314-7322 2010.  PMCID:  PMC2930196 (Project 4 and Core C)

    Cavigiolio G, Geier EG, Shao B, Heinecke JW, Oda MN:  Exchange of apolipoprotein A-I between lipid-associated and lipid-free states:  A potential target for oxidative generation of dysfunctional high density lipoproteins.  J Biol Chem 285:18847-18857, 2010. PMCID:  PMC2881807 (Project 4 and Core C)

    Shao B, Pennathur S, Pagani I, Oda MN, Witztum JL, Oram JF, Heinecke JW:  Modifying apolipoprotein A-I by malondialdehyde, but not by an array of other reactive carbonyls, blocks cholesterol efflux by the ABCA1 pathway.  J Biol Chem 285:18473-18484, 2010.  PMCID:  PMC2881773 (Projects 3 and 4, and Core C)

    Becker L, Gharib SA, Irwin AD, Wijsman E, Vaisar T, Oram JF, Heinecke JW:  A macrophage sterol-responsive network linked to atherogenesis.  Cell Metab 11:125-135, 2010.  PMCID:  PMC2893224 (Projects 3 and 4, and Cores B and C)

    Hoofnagle AN, Wu M, Gosmanova AK,  Becker JO, Wijsman EM, Brunzell JD, Kahn SE, Knopp RH, Lyons TJ, Heinecke JW:  Low clusterin levels in high density lipoprotein associate with insulin resistance and obesity.  Arterioscler Thromb Vasc Biol 30:2528-2534, 2010.  PMCID:  PMC2988100 (Project 4 and Core C)

    Suzuki M, Pritchard DK, Becker L, Hoofnagle AN, Tanimura N, Bammler TK, Beyer RP, Bumgarner R, Vaisar T, de Beer MC, de Beer FC, Miyake K, Oram JF, Heinecke JW:  High-density lipoprotein suppresses the type I interferon response, a family of potent antiviral immunoregulators, in macrophages challenged with lipopolysaccharide.  Circulation 122:1919-1927, 2010.  PMCID:  PMC2988582 (Projects 3 and 4, and Cores B and C)

    Averill MM, Barnhart S, Becker L, Li X, Heinecke JW, LeBoeuf RC, Hamerman JA, Sorg C, Kerkhoff C, Bornfeldt KE:  S100A9 differentially modifies phenotypic states of neutrophils, macrophages, and dendritic cells:  Implications for Atherosclerosis and Adipose Tissue Inflammation.  Circulation 123:1216-1226, 2011.  PMCID:  PMC3072335 (Projects 2, 3 and 4, and Cores B and C)

    Shao B, Heinecke JW:  Impact of HDL oxidation by the myeloperoxidase system on sterol efflux by the ABCA1 pathway.  J Proteomics 74:2289-2299, 2011.  PMCID:  PMC3156866 (Project 4 and Core C)

    Chiba T, Chang MY, Wang S, Wight TN, McMillen TS, Oram JF, Vaisar T, Heinecke JW, De Beer FC, De Beer MC, Chait A:  Serum amyloid A facilitates the binding of high-density lipoprotein from mice injected with lipopolysaccharide to vascular proteoglycans.  Arterioscler Thromb Vasc Biol 31:1326-1332, 2011.  PMCID: PMC3129975 (Projects 1, 3 and 4, and Cores B and C)

    Shao B, Pennathur S, Heinecke JW:  Myeloperoxidase targets apolipoprotein A-I, the major high density lipoprotein protein, for site-specific oxidation in human atherosclerotic lesions.  J Biol Chem 287:6375-6386, 2012.  PMCID:  PMC3307260 (Project 4 and Core C)

    Kanter JE, Kramer F, Barnhart S, Averill MM, Vivekanandan-Giri A, Vickery T, Li LO, Becker L, Yuan W, Chait A, Braun KR, Potter-Perigo S, Sanda S, Wight TN, Pennathur S, Serhan CN, Heinecke JW, Coleman RA, Bornfeldt KE:  Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1.  Proc Natl Acad Sci USA 109:E715-724, 2012.  PMCID:  PMC3311324 (Projects 1, 2 and 4, and Cores B and C)

    Becker L, Liu NC, Averill MM, Yuan W, Pamir N, Peng Y, Irwin AD, Fu X, Bornfeldt KE, Heinecke JW:  Unique proteomic signatures distinguish macrophages and dendritic cells.  PLoS One 7:e33297, 2012.  PMCID:  PMC3299764 (Projects 2 and 4, and Cores B and C)

    Suzuki M, Becker L, Pritchard DK, Gharib SA, Wijsman EM, Bammler TK, Beyer RP, Vaisar T, Oram JF, Heinecke JW:  Cholesterol accumulation regulates expression of macrophage proteins implicated in proteolysis and complement activation.  Arterioscler Thromb Vasc Biol 32:2910-2918, 2012.  PMCID:  PMC3501207 (Projects 3 and 4, and Cores B and C)

    Rubinow KB, Vaisar T, Tang C, Matsumoto AM, Heinecke JW, Page ST:  Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J Lipid Res 53:1376-83, 2012. PMCID: PMC3371249 (Projects 3 and 4, and Core C)

    Page ST, Krauss RM, Gross C, Ishida B, Heinecke JW, Tang C, Amory JK, Schaefer PM, Cox CJ, Kane J, Purnell JQ, Weinstein RL, Vaisar T:  Impact of mifepristone, a glucocorticoid/progesterone antagonist, on HDL cholesterol, HDL particle concentration, and HDL function. J Clin Endocrinol Metab 97:1598-1605, 2012.  PMCID: PMC3339893 (Projects 3 and 4, and Core C)

    Rubinow KB, Tang C, Hoofnagle AN, Snyder CN, Amory JK, Heinecke JW, Page ST:  Acute sex steroid withdrawal increases cholesterol efflux capacity and HDL-associated clusterin in men. Steroids 77:454-460, 2012.  PMCID: PMC3304018 (Projects 3 and 4, and Core C)

    Heinecke JW:  HDL’s protein cargo:  Friend or foe in cardioprotection? Circulation 127:868-869, 2013. (Editorial) (Project 4 and Core C)

    Vivekanandan-Giri A, Slocum JL, Byun J, Tang C, Sands RL, Gillespie BW, Heinecke JW, Saran R, Kaplan MJ, Pennathur S:  High density lipoprotein is targeted for oxidation by myeloperoxidase in rheumatoid arthritis. Ann Rheum Dis 72:1725-1731, 2013.  PMID:  23313808 (Projects 3 and 4, Core C)

    Driscoll, WS, Vaisar T, Tang J, Wilson CL, Raines EW:  Macrophage ADAM17 deficiency augments CD36-dependent apoptotic cell uptake and the linked anti-inflammatory phenotype.  Circ Res 113:52-61, 2013.  PMCID:  PMC3693752 (Core C)

    Lee JT, Pamir N, Liu NC, Kirk EA, Averill MM, Becker L, Larson I, Hagman DK, Foster-Schubert KE, van Yserloo B, Bornfeldt KE, LeBoeuf RC, Kratz M, Heinecke JW: Macrophage metalloelastase (Mmp12) regulates adipose tissue expansion, insulin sensitivity, and the expression of inducible nitric oxide synthase. Endocrinology In press. (Projects 2, 3 and 4, and Cores B and C)