Neil J. Freedman, MD

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Services

• General and Consultative Heart Care

Department / Division:
Medicine / Cardiovascular Medicine

Address:
DUMC 3187
Durham, NC 27710

Appointment Telephone:
(919) 681-5816

Office Telephone:
(919) 684-6873

Fax Telephone:
(919) 684-6870

• M.D., 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, North Carolina, 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.  Specifically, we are investigating (i) the regulation of receptor protein tyrosine kinases by G protein-coupled receptor kinases (GRKs); (ii) the role of tumor necrosis factor and its receptors in atherosclerosis; (iii) the atherogenicity of novel genes associated statistically with atherosclerosis by our genetic epidemiology colleagues.  For in vivo modeling of atherosclerosis and neointimal hyperplasia, we study the aortas of atherogenic mice with various gene deletions, and perform mouse carotid artery bypass grafting with either veins or arteries from gene-deleted or congenic wild type mice.  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, desensitization, phosphorylation, platelet-derived growth factor receptors, receptor protein tyrosine kinases, smooth muscle cells, neointimal hyperplasia, LDL receptors.

Representative Publications:
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

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

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

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

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

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

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

Freedman NJ, Lefkowitz RJ. Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation. J Clin Invest. 2004 May;113(10):1379-82. (2004) 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

Freedman NJ, Ginsburg GS. Novel--and "neu"--therapeutic possibilities for heart failure. J Am Coll Cardiol. 2006 Oct 3;48(7):1448-50. (2006) 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

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

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