Neil J. Freedman, MD


Associate Professor of Medicine
Department / Division:
Medicine / Medicine - Cardiology
Address:
DUMC 3187
Durham, NC 27710
Appointment Telephone:
919-681-5816
Office Telephone:
919-681-5821
Fax:
919-684-6870
Training:
  • MD, Harvard Medical School (Massachusetts), 1985
Residency:
  • Medicine, Beth Israel Hospital (Massachusetts), 1985-1988
Fellowship:
  • Medicine (Research), Brigham and Women's Hospital (Massachusetts), 1988-1990
  • Cardiology, Duke University Medical Center, 1990-1993
Clinical Interests:
Preventive cardiology; lipid disorders
Research Interests:
Our work focuses on atherosclerosis-related signal transduction and the genetic bases of atherosclerosis and vein graft failure, both in vitro and in vivo. We investigate the regulation of receptor protein tyrosine kinases by G protein-coupled receptor kinases (GRKs), and the role of GRKs and β-arrestins in atherosclerosis; the role of tumor necrosis factor and its receptors in atherosclerosis; and the role of the dual Rho-GEF kalirin in atherosclerosis. For in vivo modeling of atherosclerosis and neointimal hyperplasia, we use mouse carotid artery bypass grafting with either veins or arteries from gene-deleted or congenic wild type mice, as well as aortic atherosclerosis studies and bone marrow transplantation. To study receptor phosphorylation, signal transduction, and intracellular trafficking, we employ primary smooth muscle cells, endothelial cells, and macrophages derived from knockout mice or treated with RNA interference.

Key Words: atherosclerosis, G protein-coupled receptor kinases, arrestins, desensitization, phosphorylation, platelet-derived growth factor receptors, receptor protein tyrosine kinases, smooth muscle cells, neointimal hyperplasia, Rho-GEF.
Representative Publications:
  • Brown, MA; Zhang, L; Levering, VW; Wu, JH; Satterwhite, LL; Brian, L; Freedman, NJ; Truskey, GA. Human umbilical cord blood-derived endothelial cells reendothelialize vein grafts and prevent thrombosis. Arteriosclerosis, Thrombosis and Vascular Biology. 2010;30:2150-2155.  Abstract
  • Zhang, L; Connelly, JJ; Peppel, K; Brian, L; Shah, SH; Nelson, S; Crosslin, DR; Wang, T; Allen, A; Kraus, WE; Gregory, SG; Hauser, ER; Freedman, NJ. Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies. Human Molecular Genetics. 2010;19:2754-2766.  Abstract
  • Cai, X; Wu, JH; Exum, ST; Oppermann, M; Premont, RT; Shenoy, SK; Freedman, NJ. Reciprocal regulation of the platelet-derived growth factor receptor-beta and G protein-coupled receptor kinase 5 by cross-phosphorylation: effects on catalysis. Molecular Pharmacology. 2009;75:626-636.  Abstract
  • Shah, SH; Freedman, NJ; Zhang, L; Crosslin, DR; Stone, DH; Haynes, C; Johnson, J; Nelson, S; Wang, L; Connelly, JJ; Muehlbauer, M; Ginsburg, GS; Crossman, DC; Jones, CJ; Vance, J; Sketch, MH; Granger, CB; Newgard, CB; Gregory, SG; Goldschmidt-Clermont, PJ; Kraus, WE; Hauser, ER. Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis. PLoS Genetics. 2009;5:e1000318.  Abstract
  • Kim, J; Zhang, L; Peppel, K; Wu, JH; Zidar, DA; Brian, L; DeWire, SM; Exum, ST; Lefkowitz, RJ; Freedman, NJ. Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circulation Research. 2008;103:70-79.  Abstract
  • Zhang, L; Sivashanmugam, P; Wu, JH; Brian, L; Exum, ST; Freedman, NJ; Peppel, K. Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery. Arteriosclerosis, Thrombosis and Vascular Biology. 2008;28:284-289.  Abstract
  • Zhang, L; Peppel, K; Sivashanmugam, P; Orman, ES; Brian, L; Exum, ST; Freedman, NJ. Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis. Arteriosclerosis, Thrombosis and Vascular Biology. 2007;27:1087-1094.  Abstract
  • Wu, JH; Goswami, R; Cai, X; Exum, ST; Huang, X; Zhang, L; Brian, L; Premont, RT; Peppel, K; Freedman, NJ. Regulation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-5 in vascular smooth muscle cells involves the phosphatase Shp2. Journal of Biological Chemistry. 2006;281:37758-37772.  Abstract
  • Peppel, K; Zhang, L; Orman, ES; Hagen, PO; Amalfitano, A; Brian, L; Freedman, NJ. Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms. Cardiovascular Research. 2005;65:674-682.  Abstract
  • Wu, JH; Goswami, R; Kim, LK; Miller, WE; Peppel, K; Freedman, NJ. The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition. Journal of Biological Chemistry. 2005;280:31027-31035.  Abstract
  • Hildreth, KL; Wu, JH; Barak, LS; Exum, ST; Kim, LK; Peppel, K; Freedman, NJ. Phosphorylation of the platelet-derived growth factor receptor-beta by G protein-coupled receptor kinase-2 reduces receptor signaling and interaction with the Na(+)/H(+) exchanger regulatory factor. Journal of Biological Chemistry. 2004;279:41775-41782.  Abstract
  • Zhang, L; Freedman, NJ; Brian, L; Peppel, K. Graft-extrinsic cells predominate in vein graft arterialization. Arteriosclerosis, Thrombosis and Vascular Biology. 2004;24:470-476.  Abstract
  • Zhang, L; Peppel, K; Brian, L; Chien, L; Freedman, NJ. Vein graft neointimal hyperplasia is exacerbated by tumor necrosis factor receptor-1 signaling in graft-intrinsic cells. Arteriosclerosis, Thrombosis and Vascular Biology. 2004;24:2277-2283.  Abstract
  • Wu, JH; Peppel, K; Nelson, CD; Lin, FT; Kohout, TA; Miller, WE; Exum, ST; Freedman, NJ. The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor. Journal of Biological Chemistry. 2003;278:44238-44245.  Abstract
  • Freedman, NJ; Kim, LK; Murray, JP; Exum, ST; Brian, L; Wu, JH; Peppel, K. Phosphorylation of the platelet-derived growth factor receptor-beta and epidermal growth factor receptor by G protein-coupled receptor kinase-2. Mechanisms for selectivity of desensitization. Journal of Biological Chemistry. 2002;277:48261-48269.  Abstract
  • Peppel, K; Zhang, L; Huynh, TT; Huang, X; Jacobson, A; Brian, L; Exum, ST; Hagen, PO; Freedman, NJ. Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells reduces neointimal hyperplasia. Journal of Molecular and Cellular Cardiology. 2002;34:1399-1409.  Abstract
  • Zhang, L; Hagen, PO; Kisslo, J; Peppel, K; Freedman, NJ. Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model. Journal of Vascular Surgery. 2002;36:824-832.  Abstract
  • Peppel, K; Jacobson, A; Huang, X; Murray, JP; Oppermann, M; Freedman, NJ. Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells attenuates mitogenic signaling via G protein-coupled and platelet-derived growth factor receptors. Circulation. 2000;102:793-799.  Abstract
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