Department / Division:
Medicine / Cardiology

Address:
DUMC 3187
Durham, NC 27710

Appointment Telephone:
919-681-5816

Office Telephone:
919-684-6873

Fax Telephone:
919-684-6870

• MD, Harvard Medical School (Massachusetts), 1985

• Medicine, Beth Israel Hospital (Massachusetts), 1985-1988

• Research Fellow in Medicine, 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:
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 Genet. 2009 Jan;5(1):e1000318. (2009) 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. Mol Pharmacol. 2009 Mar;75(3):626-36. (2009) Abstract

Wang L, Hauser ER, Shah SH, Seo D, Sivashanmugam P, Exum ST, Gregory SG, Granger CB, Haines JL, Jones CJ, Crossman D, Haynes C, Kraus WE, Freedman NJ, Pericak-Vance MA, Goldschmidt-Clermont PJ, Vance JM. Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease. Ann Hum Genet. 2008 Jul;72(Pt 4):443-53. (2008) Abstract

Shenoy SK, Xiao K, Venkataramanan V, Snyder PM, Freedman NJ, Weissman AM. Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor. J Biol Chem. 2008 Aug 8;283(32):22166-76. (2008) 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. Circ Res. 2008 Jul 3;103(1):70-9. (2008) 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. Arterioscler Thromb Vasc Biol. 2007 Nov 15. (2007) 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. Arterioscler Thromb Vasc Biol. 2007 May;27(5):1087-94. (2007) Abstract

Vinge LE, Andressen KW, Attramadal T, Andersen GØ, Ahmed MS, Peppel K, Koch WJ, Freedman NJ, Levy FO, Skomedal T, Osnes JB, Attramadal H. Substrate specificities of g protein-coupled receptor kinase-2 and -3 at cardiac myocyte receptors provide basis for distinct roles in regulation of myocardial function. Mol Pharmacol. 2007 Sep;72(3):582-91. (2007) 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. J Biol Chem. 2006 Dec 8;281(49):37758-72. (2006) 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.  J Biol Chem.  2005 Sep 2;280(35):31027-35. (2005) 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. Cardiovasc Res. 2005 Feb 15;65(3):674-82. (2005) 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.  Arterioscler Thromb Vasc Biol.  2004 Dec;24(12):2277-83. (2004) Abstract

Zhang L, Freedman NJ, Brian L, Peppel K. Graft-extrinsic cells predominate in vein graft arterialization.  Arterioscler Thromb Vasc Biol.  2004 Mar;24(3):470-6. (2004) 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.  J Biol Chem.  2004 Oct 1;279(40):41775-82. (2004) 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. J Biol Chem. 2003 Nov 7;278(45):44238-45. (2003) Abstract

Zhang L, Hagen PO, Kisslo J, Peppel K, Freedman NJ. Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model. J Vasc Surg. 2002 Oct;36(4):824-32. (2002) 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. J Mol Cell Cardiol. 2002 Oct;34(10):1399-1409. (2002) 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. J Biol Chem. 2002 Dec 13;277(50):48261-9. (2002) Abstract