Our Research: Faculty/Research Laboratories

Karin Bornfeldt, PhD

Professor of Medicine, Division of Metabolism, Endocrinology and Nutrition

Professor, Department of Pathology

Associate Director, Diabetes and Obesity Center of Excellence

Deputy Director, Diabetes Research Center

Email Address: bornf@u.washington.edu

Division of Metabolism, Endocrinology and Nutrition Website:  http://depts.washington.edu/metab/
Pathology Department Website: http://www.pathology.washington.edu/

Background:

Karin Bornfeldt received her PhD from Linköping University in Sweden in 1991. Later that year, she came to the University of Washington to do a postdoctoral fellowship in the laboratory of Dr. Russell Ross, a leader in the field of cardiovascular medicine.  She also worked closely with Dr. Edwin Krebs on phosphorylation of signal transduction proteins in vascular cells.  She was appointed to the faculty in 1995, and is now Professor of Medicine and Pathology and serves as the Associate Director of the Diabetes and Obesity Center of Excellence and Deputy Director of the Diabetes Research Center.

Dr. Bornfeldt is actively involved in graduate student teaching and has served on more than 20 Doctoral Supervisory Committees in Pathology, Molecular and Cellular Biology, Pharmacology, and Nutritional Sciences.

Dr. Bornfeldt frequently serves on study sections on cardiovascular biology and the complications of diabetes at the NIH and the American Heart Association.  She is a Fellow of the Council of Basic Cardiovascular Sciences, American Heart Association, is Consulting Editor for Arteriosclerosis, Thrombosis and Vascular Biology, Associate Editor for Circulation Research, and is or has been a member of the editorial boards of the Journal of Clinical Investigation, Circulation Research, Diabetes, and the Journal of Biological Chemistry.

For additional information on Dr. Bornfeldt’s lab, please visit her lab website.

 

Focus:

People with type 1 or type 2 diabetes/insulin resistance have a greater risk of developing cardiovascular disease (myocardial infarction, stroke, and peripheral cardiovascular disease that can lead to the necessity to amputate limbs).  The cardiovascular disease is caused primarily by atherosclerosis.  These cardiovascular complications also develop earlier in life compared to people without diabetes.  Risk factors for cardiovascular disease associated with diabetes include inflammatory changes, sub-optimal metabolic control and lipid abnormalities, such as increased levels of triglycerides and fatty acids, and decreased levels of HDL cholesterol.  Dr. Bornfeldt’s research focuses on understanding the mechanisms of diabetes-accelerated atherosclerosis so that cardiovascular complications can be treated or prevented.

Dr. Bornfeldt’s laboratory has shown, using a mouse model of type 1 diabetes-accelerated atherosclerosis, that diabetes stimulates both initiation of lesions of atherosclerosis and progression to advanced lesions.  The working hypothesis is that diabetes stimulates lesion initiation and progression by increasing recruitment of inflammatory cells and arterial inflammation.

More resent research by Dr. Bornfeldt’s group has identified a key step in the mechanism of diabetes-induced inflammatory changes and atherosclerosis. The culprit, acyl-CoA synthetase 1, is an enzyme that converts free fatty acids into their acyl-CoA derivatives in myeloid cells. Current research focuses on the role glucose and acyl-CoAs might play in endothelial dysfunction, inflammation and diabetes-accelerated atherosclerosis.  Dr. Bornfeldt is also interested in other inflammatory biomarkers and mediators in relation to both type 1 and type 2 diabetes, and insulin resistance.

Dr. Bornfeldt’s research has been continuously funded by the National Heart, Lung, and Blood Institute (NIH). Other funding sources include, or have included, the Juvenile Diabetes Research Foundation, the American Heart Association, the American Diabetes Association, Novo Nordisk A/S, Seattle Foundation, and the Royalty Research Fund at the University of Washington.

 

Representative Publications:

Renard CB, Kramer F, Johansson F, Lamharzi N, Tannock LR, von Herrath MG, Chait A, Bornfeldt KE (2004): Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest. 114, 659-668. PMCID: PMC514580.

Johansson F, Kramer F, Barnhart S, Kanter JE, Vaisar T, Merrill RD, Geng L, Oka K, Chan L, Chait A, Heinecke JW & Bornfeldt KE (2008): Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice. Proc Natl Acad Sci USA. 105, 2082-2087. PMCID: PMC2538884.

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

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 (2012): Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1. Proc Natl Acad Sci U S A. 109, E715-E724. PMCID: PMC23311234.

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 (2014): Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep. 7, 356-365. PMCID: PMC4021396

  • Bornfeldt KE, Gidlöf RA, Wasteson Å, Lake M, Skottner A & Arnqvist HJ (1991): Binding and biological effects of insulin, insulin analogues and insulin-like growth factors in rat aortic smooth muscle cells. Comparison of maximal growth promoting activities. Diabetologia. 34, 307-313.

    Bornfeldt KE, Raines EW, Nakano T, Graves LM, Krebs EG & Ross R (1994): Insulin-like growth factor-I and platelet-derived growth factor-BB inducedirected migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation. J Clin Invest. 93,1266-1274.

    Bornfeldt KE, Graves LM, Raines EW, Igarashi Y, Wayman G, Yamamura S, Yatomi Y, Sidhu JS, Krebs EG, Hakomori S & Ross R (1995): Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: Spatial and temporal modulation of PDGF chemotactic signal transduction. J. Cell Biol. 130, 193-206.

    Graves LM, Bornfeldt KE, Argast GM, Krebs EG, Kong X, Lin TA & Lawrence JC Jr (1995): cAMP- and rapamycin-sensitive regulation of the association ofeukaryotic initiation factor 4E and the translational regulator PHAS-1 in aortic smooth muscle cells. Proc Natl Acad Sci USA. 92, 7222-7226.

    Graves LM, Bornfeldt KE, Sidhu JS, Argast GM, Raines EW, Ross R, Leslie CC & Krebs EG (1996): Platelet-derived growth factor stimulates protein kinase Athrough a mitogen-activated protein kinase dependent pathway in human arterial smooth muscle cells. J Biol Chem. 271, 505-511.

    Koyama H, Raines EW, Bornfeldt KE, Roberts JM & Ross R (1996): Fibrillar collagen inhibits arterial smooth muscle proliferation through regulation ofcdk2 inhibitors. Cell. 87, 1069-1078.

    Bornfeldt KE, Campbell JS, Koyama H, Argast GM, Leslie CC, Raines EW, Krebs EG & Ross R (1997): The mitogen-activated protein kinase pathway can mediate growth inhibition and proliferation in smooth muscle cells: Dependence on the availability of downstream targets. J Clin Invest. 100, 875-885.

    Rybalkin SD, Bornfeldt KE, Sonnenburg WK, Rybalkina IG, Kwak KS, Hanson K, Krebs EG & Beavo JA (1997): Calmodulin-stimulated cyclic nucleotidephosphodiesterase (PDE1C) is induced in human arterial smooth muscle cells of the synthetic, proliferative phenotype. J Clin Invest. 100, 2611-2621.

    Zhao AZ, Bornfeldt KE & Beavo JA (1998): Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest. 102, 869-873.

    Zhao AZ, Shinohara MM, Huang D, Eldar-Finkelman H, Krebs EG, Beavo JA & Bornfeldt KE (2000): Leptin induces insulin-like signaling that antagonizes cAMP elevation by glucagon in hepatocytes. J Biol Chem. 275, 11348-11354.

    Suzuki LA, Poot M, Gerrity RG & Bornfeldt KE (2001): Diabetes accelerates smooth muscle accumulation in atherosclerotic lesions: Lack of direct growthpromoting effects of high glucose levels. Diabetes. 50, 851-860.

    Renard CB & Bornfeldt KE (2001): Human arterial smooth muscle cells rapidly deplete cell culture media of glucose. Diabetologia. 44, 1067-1068.

    Wong ST, Baker LP, Trinh K, Hetman M, Suzuki LA, Storm DR & Bornfeldt KE (2001): Adenylyl cyclase 3 mediates prostaglandin E2-induced growth inhibitionin arterial smooth muscle cells. J Biol Chem. 276, 34206-34212.

    Rybalkin SD, Rybalkina IG, Beavo JA & Bornfeldt KE (2002): Calmodulin-dependent cyclic nucleotide phosphodiesterase 1C promotes human arterial smooth muscle cell proliferation. Circ Res. 90, 151-157.

    Askari B, Renard CB & Bornfeldt KE (2002): Regulation of smooth muscle accumulation in diabetes-accelerated atherosclerosis. Histol Histopathol. 17,1317-1328.

    Askari B, Carroll MA, Capparelli M, Kramer F, Gerrity RG & Bornfeldt KE (2002): Oleate and linoleate enhance the growth-promoting effects of IGF-Ithrough a phospholipase D-dependent pathway in arterial smooth muscle cells. J Biol Chem. 277, 36338-36344.

    Bornfeldt KE (2003): The cyclin-depentent kinase pathway moves forward. Circ Res. 92, 345-347.

    Yokota T, Ma R, Park J-Y, Isshiki K, Sotiropoulos K, Raunniyar R, Bornfeldt KE & King GL (2003): Role of protein kinase C on the expression ofplatelet-derived growth factor and endothelin-1 in the retina of diabetic rats and cultured retinal capillary pericytes. Diabetes. 52, 838-845.

    Renard CB, Askari B, Suzuki LA, Kramer F & Bornfeldt KE (2003): Oleate, not ligands for the receptor of advanced glycation end-products, promotesproliferation of human arterial smooth muscle cells. Diabetologia. 46, 1676-1687.

    Rybalkin SD, Chen Y, Bornfeldt KE & Beavo JA (2003): Cyclic GMP-phosphodiesterases and regulation of arterial smooth muscle function. Circ Res. 93,280-291.

    Oram JF & Bornfeldt KE (2004): Direct effects of long-chain non-esterified fatty acids on vascular cells and relevance to macrovascular complications ofdiabetes. Front Biosci. 9, 1240-1353.

    Lamharzi N, Renard CB, Kramer F, Pennathur S, Heinecke JW, Chait A & Bornfeldt KE (2004): Hyperlipidemia in concert with hyperglycemia stimulates the proliferation of macrophages in atherosclerotic lesions: Potential role of glucose-oxidized LDL. Diabetes. 53, 3217-3225.

    Renard CB, Kramer F, Johansson F, Lamharzi N, Tannock LR, von Herrath MG, Chait A, Bornfeldt KE (2004): Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest. 114, 659-668.

    Mashek DG, Bornfeldt KE, Coleman RA, Berger J, Bernlohr DA, Black P, DiRusso CC, Farber SA, Guo W, Hashimoto N, Khodiyar V, Kuypers FA, Maltais LJ,Nebert DW, Renieri A, Schaffer JE, Stahl A, Watkins PA, Vasiliou V, Yamamoto TT (2004): Revised nomenclature for the mammalian long-chain acyl-CoA synthetase gene family. J Lipid Res. 45, 1958-1961.

    Dekker Nitert M, Chisalita SI, Olsson K, Bornfeldt KE & Arnqvist HJ (2005): IGF-I/insulin hybrid receptors in human endothelial cells. Mol Cell Endocrinol. 229, 31-37.

    Bornfeldt KE (2006): Nuclear signaling in smooth muscle cells: cyclic nucleotide phosphodiesterase 1A moves in. Circ Res. 98, 720-722.

    MacDougall ED, Kramer F, Polinsky P, Barnhart S, Askari B, Johansson F, Rosenfeld ME, Oka K, Chan L, Schwartz SM & Bornfeldt KE (2006): Aggressive very low-density lipoprotein (VLDL) and LDL lowering by gene transfer of the VLDL receptor combined with a low fat diet regimen induces regression and reducesmacrophage content in advanced atherosclerotic lesions in LDL receptor-deficient mice. Am J Pathol. 168, 2064-2073.

    Bornfeldt KE (2006): A single second messenger. Several possible cellular responses depending on distinct subcellular pools. Circ Res. 99, 790-792.

    Askari B, Kanter JE, Sherrid AM, Golej DL, Bender AT, Liu J, Hsueh WA, Beavo JA, Coleman RA & Bornfeldt KE (2007): Rosiglitazone inhibits acyl-CoA synthetase activity and fatty acid partitioning to diacylglycerol and triacylglycerol via a PPAR-independent mechanism in human arterial smooth muscle cells and macrophages. Diabetes. 56, 1143-1152.

    Kanter JE, Johansson F, LeBoeuf RC & Bornfeldt KE (2007): Do glucose and lipids exert independent effects on atherosclerotic lesion initiation or progression to advanced plaques? Circ Res. 100, 769-781.

    Shen X & Bornfeldt KE (2007): Mouse models for cardiovascular complications of type 1 diabetes. Ann New York Acad Sci. 1103, 202-217.

    Johansson F, Kramer F, Barnhart S, Kanter JE, Vaisar T, Merrill RD, Geng L, Oka K, Chan L, Chait A, Heinecke JW & Bornfeldt KE (2008): Type 1 diabetes promotes disruption of advanced atherosclerotic lesions in LDL receptor-deficient mice. Proc Natl Acad Sci USA. 105, 2082-2087.

    Zeng H, Horie K, Madisen L, Pavlova MN, Gragerova G, Rohde AD, Schimpf BA, Liang Y, Ojala E, Kramer F, Roth P, Slobodskaya O, Dolka I, Southon EA, Tessarollo L, Bornfeldt KE, Gragerov A, Pavlakis GN, Gaitanaris GA (2008): An inducible and reversible mouse genetic rescue system. PLoS Genet., e1000069, 1-13.

    Kanter JE, Averill MM, LeBoeuf RC & Bornfeldt, KE (2008): Diabetes-accelerated atherosclerosis and inflammation. Circ Res. 103, e116-e117.

    Chait A, Bornfeldt KE (2009): Diabetes and atherosclerosis: Is there a role for hyperglycemia? J Lipid Res. 50 Suppl, S335-339.

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

    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 (2009): 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.

    Tang C, Kanter JE, Bornfeldt KE, Leboeuf RC, Oram JF (2010): Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys. J Lipid Res. 51, 1719-1728.

    Cardoso LE, Little PJ, Ballinger ML, Chan CK, Braun KR, Potter-Perigo S, Bornfeldt KE, Kinsella MG, Wight TN (2010): Platelet-derived growth factor differentially regulates the expression and post-translational modification of versican by arterial smooth muscle cells through distinct protein kinase C and extracellular signal-regulated kinase pathways. J Biol Chem. 285, 6987-6995.

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

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

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

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

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

    Kanter JE, Tang C, Oram JF, Bornfeldt KE (2012): 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.

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

    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 (2012): Diabetes promotes an inflammatory macrophage phenotype and atherosclerosis through acyl-CoA synthetase 1. Proc Natl Acad Sci U S A. 109, E715-E724.

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

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

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

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

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

    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 (2013): 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.

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

    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 (2013): 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.

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

    Goldberg IJ, Bornfeldt KE (2013): Lipids and the endothelium: bidirectional interactions. Curr Atheroscler Rep. 15, 365.

    Taborsky GJ Jr, Mei Q, Bornfeldt KE, Hackney DJ, Mundinger TO (2014): The p75 neurotrophin receptor is required for the major loss of sympathetic nerves from islets under autoimmune attack. Diabetes. 63, 2369-2379.

    Bornfeldt KE (2014): 2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis. Arterioscler Thromb Vasc Biol. 34, 705-714.

    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 (2014): Testing the role of myeloid cell glucose flux in inflammation and atherosclerosis. Cell Rep. 7, 356-365.

    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 (2014): Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821-835.

    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 (2014): Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase. Endocrinology. Jun 10:en20141037. [Epub ahead of print]

Current Collaborations:

Within the Diabetes and Obesity Center of Excellence and its Affiliated Members
Alan Chait, MD
Jay Heinecke, MD
Renee LeBoeuf, PhD
Francis Kim, MD
Tomas Vaisar, PhD

Outside of the Diabetes and Obesity Center of Excellence
Rosalind Coleman, UNC
Edward Fisher, NYU
David Ford, Saint Louis University

Lab Members:

Shelley Barnhart, BS
Jenny Kanter, PhD
Farah Kramer, BS
Ricky Rualo, BS
Sara Vallerie, PhD
Valerie Wall, BS