University of Kentucky Academic Appointments: Education: • MD, University of Hamburg, Germany Awards: • Research Fellowship, Acute Coronary Syndrome, German Society of Cardiology Specific Interest in Nutrition: Role of Nuclear Hormone Receptors in Cardiovascular Complications of Obesity and Diabetes. Research: Cardiovascular disease is the leading cause of death in the nation and industrialized nations, accounting for nearly 50% of all deaths. Particularly, diabetes is associated with significantly accelerated rates of cardiovascular complications. According to the Center for Disease Control and Prevention 18.3 % of all people age 60 years or older had diabetes in 2002 and an estimated 65 % of patients with diabetes ultimately die from cardiovascular causes. With the recognition of this evidence, understanding the mechanisms leading to diabetic vascular complications has become a focus of our research laboratory. We are particularly interested in characterizing the molecular pathways by which members of the nuclear hormone receptors superfamily, such as the peroxisome proliferator-activated receptor-gamma (PPARγ) or Liver X Receptors (LXR), suppress the expression of genes involved in the development of cardiovascular disease in diabetes. Our laboratory has primarily focused on understanding the regulation of vascular smooth muscle cell proliferation and inflammation by these receptors. Understanding these mechanisms is of considerable interest as these nuclear transcription factors can be pharmacologically activated by agents already clinically used to treat insulin-resistance in patients with type 2 diabetes and dyslipidemia, two of the most common cardiovascular risk factors. Since these drugs are currently being further investigated in large randomized trials for their efficacy to prevent cardiovascular disease, our research might point to molecular mechanisms by which these agents prevent the development of cardiovascular complications in patients with diabetes. Representative Publications: 1. Bruemmer D, Evans D, Berg D, Greten H, Beisiegel U, Mann WA. Expression of type III hyperlipoproteinemia in patients homozygous for apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia. J Mol Med 1998; 76: 355-364 2. Goetze S, Blaschke F, Stawowy P, Bruemmer D, Spencer C, Graf K, Grafe M, Law RE, Fleck E. TNFalpha inhibits insulin’s antiapoptotic signalling in vascular smooth muscle cells. Biochem Biophys Res Commun 2001; 287: 662-70 3. Bruemmer D, Riggers U, Holzmeister J, Ludewig B, Grill M, Lippek F, Settmacher U, Regitz-Zagrosek V, Fleck E, Graf K. Expression of CD40 in vascular smooth muscle cells and macrophages is associated with the early development of human atherosclerotic lesions. Am J Card 2001; 87: 21-7 4. Knecht M, Pagel I, Langenickel T, Philipp S, Scheuermann-Freestone M, Willnow T, Bruemmer D, Graf K, Dietz R, Willenbrock R. Increased expression of renal neutral endopeptidase in severe heart failure. Life Sci 2002; 71: 2701 5. Kintscher U, Lyon C, Wakino S, Bruemmer D, Feng X, Goetze S, Graf inhibits TGF-ßαK, Moustakas A, Staels B, Fleck E, Hsueh WA, Law RE. PPAR induced ß5 Integrin Transcription in vascular smooth muscle cells by interacting with Smad4. Circ Res. 2002; 91:35-44. 6. Kintscher U, Wakino S, Bruemmer D, Goetze S, Graf K, Hsueh W.A, Law RE. TGF-beta(1) induces peroxisome proliferator-activated receptor gamma1 and gamma2 expression in human THP-1 monocytes. Biochem Biophys Res Commun. 2002; 297: 794-9 7. Bruemmer D, Yin F, Liu J, Kiyono T, Fleck E, Van Herle A, Graf K, Law RE. Atorvastatin inhibits expression of minichromosome maintenance proteins in vascular smooth muscle cells. Eur J Pharmacol. 2003;462:15-23. 8. Bruemmer D, Berger JP, Liu J, Kintscher U, Wakino S, Fleck E, Moller D, Law RE. A Non-Thiazolidinedione Partial Peroxisome Ligand Inhibits Vascular Smooth Muscle Cell γ Proliferator-activated Receptor Growth. Eur J Pharmacol. 2003; 466 :225-234. 9. Bruemmer D, Yin F, Liu J, Kiyono T, Fleck E, Van Herle A, Law R. Rapamycin inhibits E2F-dependent Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells. Biochem Biophys Res Commun. 2003; 303:251-8. 10. De Dois, ST, Bruemmer D, Dilley, RJ, Jennings, GLR, Law, ligands γ RE, Little P. Inhibitory activity of clinical thiazolidinedione PPAR toward cultured internal mammary artery, radial artery and saphenous vein smooth muscle cells. Circulation. 2003; 107:2548-50. 11. Kintscher U, Bruemmer D, Blaschke F, Unger T, Law RE. p38 MAP kinase negatively regulates angiotensin II-mediated effects on cell cycle molecules in human coronary smooth muscle cells. Biochem Biophys Res Commun. 2003; 305:552-556 12. Eibl G, Bruemmer D, Okada Y, Duffy JP, Law RE, Reber HA, Hines OJ. PGE2 is generated by specific COX-2 activity and increases VEGF production in COX-2 expressing human panceatic cancer cells. Biochem Biophys Res Commun. 2003; 306:887-97. 13. Bruemmer D, Yin F, Liu J, Berger JP, Kiyono T, Chen J, Fleck E, Van Herle A, Forman BM, Law RE. Peroxisome Inhibits Expression of Minichromosome γ Proliferator-activated Receptor Maintenance Proteins in Vascular Smooth Muscle Cells. Mol Endocrinol. 2003; 17:1005-18 14. Bruemmer D, Yin F, Liu J, Berger JP, Sakai T, Chen J, Fleck E, Van Herle A, Forman BM, Law RE. Regulation of the growth arrest and DNA damage-inducible gene 45 (GADD45) by Peroxisome in Vascular Smooth Muscle Cells. γ Proliferator-activated Receptor Circ Res. 2003; 93:38-47 15. Bruemmer D, Yin F, Liu J, Kiyono T, Fleck E, Van Herle A, Law RE. Expression of Minichromosome Maintenance Proteins in Vascular Smooth Muscle Cells is ERK/MAPK-dependent. Exp Cell Res. 2003; 290:28-37 16. Bruemmer D, Collins AR, Noh G, W. W, Territo M, Arias-Magallona S, Fishbein MC, Kintscher U, Fleck E, Law RE, Hsueh WA. Angiotensin II Accelerated Atherosclerosis is Attenuated in Osteopontin Deficient Mice. J Clin Invest. 2003;112:1318-31. 17. Bruemmer D, Law RE. Thiazolidinediones and Regulation of Smooth Muscle Cell Proliferation. American Journal of Medicine. 2003; 114 Suppl 8A: 87S-92S. 18. Hsueh WA, Bruemmer, D: Implications for γ . PPAR Cardiovascular Disease. Hypertension, 2004; 43:297-305. 19. Yin F, Bruemmer D, Blaschke F, Hsueh WA, Law RE, Van Herle AJ. Signaling Pathways Involved in Induction of GADD45 Gene Expression and Apoptosis by Troglitazone in Human MCF-7 Breast Carcinoma Cells. Oncogene, 2004; 23(26):4614-23. 20. Collins AR, Schnee J, Wang W, Kim S, Fishbein MC, Bruemmer D, Law RE, Nicholas S, Ross RS, Hsueh WA. Osteopontin modulates AngII-induced fibrosis in the intact murine heart. J Am Coll Cardiol, 2003; 43(9):1698-705. 21. Blaschke F, Bruemmer D, Yin F, Takata Y, Wang W, Fishbein MC, Okura T, Higaki J, Graf K, Fleck E, Hsueh WA, Law RE. C-reactive protein induces apoptosis in human coronary vascular smooth muscle cells. Circulation, 2004; 110(5):579-87 22. Blaschke F, Bruemmer D, Law RE. Egr-1 is a Major Vascular PathogenicTranscription Factor in Atherosclerosis and Restenosis.Rev in Endocr Metab Disord, 2004; 5(3):249-54 23. Blaschke F, Bruemmer D, Law RE. Will the potential of peroxisome proliferator-activated receptor agonists be realized in the clinical setting? Clin Cardiol. 2004, (7 Suppl 4):IV3-10. 24. Blaschke F, Leppaenen O, Takata Y, Caglayan E, Liu J, Fishbein MC, Kappert K, Nakayama KI, Fleck E, Hsueh WA, Law RE, Bruemmer D. Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries. Circ Res. 2004; 95(12):e110-23. 25. Bruemmer D, Blaschke F, Law RE. New Targets for peroxisome proliferator activated receptor {gamma} in the Vessel Wall: Implications for Restenosis. Int J Obes Relat Metab Disord, 2005, 29:26-30 26. Ogawa D, Stone JF, Takata Y, Blaschke F, Chu VH, Towler DA, Law RE, Hsueh WA, Bruemmer D . Liver X Receptor Agonists inhibit cytokine-induced Osteopontin Expression in Macrophages through Interference with Activator Protein-1 Signaling Pathways. Circ Res. 2005, 96:59-67.
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