Neil Jonathan Freedman | Scholars@Duke

Neil Jonathan Freedman
Professor of Medicine

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.

Current Appointments & Affiliations

Professor of Medicine, Medicine, Cardiology, Medicine 2017
Professor in Cell Biology, Cell Biology, Basic Science Departments 2017

Contact Information

447 Clin & Res Labs, Durham, NC 27710
Duke Box 3187, Durham, NC 27710
neil.freedman@duke.edu (919) 684-6873

Background
Education, Training, & Certifications
- Fellow in Cardiology, Medicine, Duke University 1990 - 1993
- Visiting Scientist, Massachusetts Institute of Technology 1989 - 1990
- Research Fellow in Medicine, Medicine, Brigham and Women's Hospital 1988 - 1989
- Medical Resident, Medicine, Beth Israel Deaconess Medical Center 1985 - 1988
- M.D., Harvard University 1985
Duke Appointment History
- Assistant Professor in Cell Biology, Cell Biology, Basic Science Departments 2005 - 2017
- Associate Professor of Medicine, Medicine, Cardiology, Medicine 2006 - 2017
- Assistant Professor of Medicine, Medicine, Cardiology, Medicine 1996 - 2006
- Associate in the Department of Medicine, Medicine, Cardiology, Medicine 1993 - 1996
Research
Selected Grants
- Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation awarded by National Institutes of Health 2017 - 2022
- Multidisciplinary Heart and Vascular Diseases awarded by National Institutes of Health 1975 - 2021
- Role of Drebrin in Atherosclerosis awarded by National Institutes of Health 2014 - 2019
- Anti-atherogenic Mechanisms of the Dual Rho-GEF Kalirin awarded by National Institutes of Health 2014 - 2018
- Regulation of B-arrestin2's pro-atherogenic activity by the deubiquitinase USP20 awarded by National Institutes of Health 2014 - 2018
- Role of Drebrin in Vascular Smooth Muscle Remodeling awarded by National Institutes of Health 2013 - 2018
- Desensitization of Vascular Receptor Tyrosine Kinases awarded by National Institutes of Health 2005 - 2012
- Mechanisms of Arterial Wall-Mediated Atherogenesis awarded by National Institutes of Health 2005 - 2009
- Aging, Atherosclerosis, and the Arterial Wall awarded by National Institutes of Health 2006 - 2009
- Inflammation in Vein Graft Disease: A Genetic Approach awarded by National Institutes of Health 2004 - 2006
- TNF-Inhibitor gene therapy for neointimal hyperplasia awarded by National Institutes of Health 2001 - 2005
- Receptor Kinase Gene Therapy for Neointimal Hyperplasia awarded by National Institutes of Health 1999 - 2004
- Receptor Kinase Gene Therapy for Neointimal Hyperplasia awarded by Department of Health and Human Services 1997 - 2001
- Receptor Kinase Gene Therapy For Neointimal Hyperplasia awarded by National Institutes of Health 1997 - 1999
- Receptor Desensitization In The Cardiovascular System awarded by National Institutes of Health 1994 - 1999
Publications & Artistic Works
Selected Publications
- Journal Articles
  - Freedman, NJ, and Shenoy, SK. "Regulation of inflammation by β-arrestins: Not just receptor tales." Cellular Signalling 41 (January 2018): 41-45. (Review) Full Text
  - Zhang, L, Wu, J-H, Otto, JC, Gurley, SB, Hauser, ER, Shenoy, SK, Nagi, K, Brian, L, Wertman, V, Mattocks, N, Lawson, JH, and Freedman, NJ. "Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells." Cardiovascular Research 113.13 (November 2017): 1551-1559. Full Text Open Access Copy
  - Smith, JS, Alagesan, P, Desai, NK, Pack, TF, Wu, J-H, Inoue, A, Freedman, NJ, and Rajagopal, S. "C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways." Molecular Pharmacology 92.2 (August 2017): 136-150. Full Text
  - Stiber, JA, Wu, J-H, Zhang, L, Nepliouev, I, Zhang, Z-S, Bryson, VG, Brian, L, Bentley, RC, Gordon-Weeks, PR, Rosenberg, PB, and Freedman, NJ. "The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia." Arteriosclerosis, Thrombosis, and Vascular Biology 36.5 (May 2016): 984-993. Full Text
  - Jean-Charles, P-Y, Zhang, L, Wu, J-H, Han, S-O, Brian, L, Freedman, NJ, and Shenoy, SK. "Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of β-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor κB (NFκB) Activation." The Journal of biological chemistry 291.14 (April 2016): 7450-7464. Full Text
  - Jean-Charles, P-Y, Freedman, NJ, and Shenoy, SK. "Chapter Nine - Cellular Roles of Beta-Arrestins as Substrates and Adaptors of Ubiquitination and Deubiquitination." Progress in Molecular Biology and Translational Science 141 (January 2016): 339-369. (Review) Full Text
  - Lu, Y, Zhang, L, Liao, X, Sangwung, P, Prosdocimo, DA, Zhou, G, Votruba, AR, Brian, L, Han, YJ, Gao, H, Wang, Y, Shimizu, K, Weinert-Stein, K, Khrestian, M, Simon, DI, Freedman, NJ, and Jain, MK. "Kruppel-like factor 15 is critical for vascular inflammation." The Journal of Clinical Investigation 123.10 (October 2013): 4232-4241. Full Text
  - Chandra, R, Wang, Y, Shahid, RA, Vigna, SR, Freedman, NJ, and Liddle, RA. "Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion." The Journal of Clinical Investigation 123.8 (August 2013): 3343-3352. Full Text
  - Wu, J-H, Fanaroff, AC, Sharma, KC, Smith, LS, Brian, L, Eipper, BA, Mains, RE, Freedman, NJ, and Zhang, L. "Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells." Arteriosclerosis, Thrombosis, and Vascular Biology 33.4 (April 2013): 702-708. Full Text
  - Han, S-O, Xiao, K, Kim, J, Wu, J-H, Wisler, JW, Nakamura, N, Freedman, NJ, and Shenoy, SK. "MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors." J Cell Biol 199.5 (November 26, 2012): 817-830. Full Text Link to Item
  - Zhang, L, Brian, L, and Freedman, NJ. "Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells." J Vasc Surg 56.5 (November 2012): 1390-1397. Full Text Link to Item
  - Wu, J-H, Zhang, L, Fanaroff, AC, Cai, X, Sharma, KC, Brian, L, Exum, ST, Shenoy, SK, Peppel, K, and Freedman, NJ. "G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors." Arteriosclerosis, Thrombosis, and Vascular Biology 32.2 (February 2012): 308-316. Full Text
  - Brown, MA, Zhang, L, Levering, VW, Wu, J-H, Satterwhite, LL, Brian, L, Freedman, NJ, and Truskey, GA. "Human umbilical cord blood-derived endothelial cells reendothelialize vein grafts and prevent thrombosis." Arteriosclerosis, Thrombosis, and Vascular Biology 30.11 (November 2010): 2150-2155. Full Text
  - Zhu, S, Malhotra, A, Zhang, L, Deng, S, Zhang, T, Freedman, NJ, Storms, R, Peppel, K, Goldschmidt-Clermont, PJ, and Dong, C. "Human umbilical cord blood endothelial progenitor cells decrease vein graft neointimal hyperplasia in SCID mice." Atherosclerosis 212.1 (September 2010): 63-69. Full Text Link to Item
  - Zhang, L, Connelly, JJ, Peppel, K, Brian, L, Shah, SH, Nelson, S, Crosslin, DR, Wang, T, Allen, A, Kraus, WE, Gregory, SG, Hauser, ER, and Freedman, NJ. "Aging-related atherosclerosis is exacerbated by arterial expression of tumor necrosis factor receptor-1: evidence from mouse models and human association studies." Hum Mol Genet 19.14 (July 15, 2010): 2754-2766. Full Text Link to Item
  - Cai, X, Wu, J-H, Exum, ST, Oppermann, M, Premont, RT, Shenoy, SK, and 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 75.3 (March 2009): 626-636. Full Text
  - 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, CJH, Vance, J, Sketch, MH, Granger, CB, Newgard, CB, Gregory, SG, Goldschmidt-Clermont, PJ, Kraus, WE, and Hauser, ER. "Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis." Plos Genetics 5.1 (January 2, 2009): e1000318-null. Full Text Open Access Copy
  - Shenoy, SK, Xiao, K, Venkataramanan, V, Snyder, PM, Freedman, NJ, and Weissman, AM. "Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor." The Journal of Biological Chemistry 283.32 (August 2008): 22166-22176. Full Text
  - Wang, L, Hauser, ER, Shah, SH, Seo, D, Sivashanmugam, P, Exum, ST, Gregory, SG, Granger, CB, Haines, JL, Jones, CJH, Crossman, D, Haynes, C, Kraus, WE, Freedman, NJ, Pericak-Vance, MA, Goldschmidt-Clermont, PJ, and Vance, JM. "Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease." Annals of Human Genetics 72.Pt 4 (July 3, 2008): 443-453. Full Text
  - Kim, J, Zhang, L, Peppel, K, Wu, J-H, Zidar, DA, Brian, L, DeWire, SM, Exum, ST, Lefkowitz, RJ, and Freedman, NJ. "Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration." Circulation Research 103.1 (July 2008): 70-79. Full Text Open Access Copy
  - Zhang, L, Sivashanmugam, P, Wu, J-H, Brian, L, Exum, ST, Freedman, NJ, and Peppel, K. "Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery." Arteriosclerosis, Thrombosis, and Vascular Biology 28.2 (February 2008): 284-289. Full Text
  - Vinge, LE, Andressen, KW, Attramadal, T, Andersen, GØ, Ahmed, MS, Peppel, K, Koch, WJ, Freedman, NJ, Levy, FO, Skomedal, T, Osnes, J-B, and 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." Molecular Pharmacology 72.3 (September 2007): 582-591. Full Text
  - Zhang, L, Peppel, K, Sivashanmugam, P, Orman, ES, Brian, L, Exum, ST, and Freedman, NJ. "Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis." Arteriosclerosis, Thrombosis, and Vascular Biology 27.5 (May 2007): 1087-1094. Full Text
  - Wu, J-H, Goswami, R, Cai, X, Exum, ST, Huang, X, Zhang, L, Brian, L, Premont, RT, Peppel, K, and 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." The Journal of Biological Chemistry 281.49 (December 2006): 37758-37772. Full Text
  - Freedman, NJ, and Ginsburg, GS. "Novel--and "neu"--therapeutic possibilities for heart failure." J Am Coll Cardiol 48.7 (October 3, 2006): 1448-1450. Full Text Link to Item
  - Cai, X, and Freedman, NJ. "New therapeutic possibilities for vein graft disease in the post-edifoligide era." Future Cardiol 2.4 (July 2006): 493-501. Full Text Link to Item
  - Wu, J-H, Goswami, R, Kim, LK, Miller, WE, Peppel, K, and Freedman, NJ. "The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition." The Journal of Biological Chemistry 280.35 (September 2005): 31027-31035. Full Text
  - Peppel, K, Zhang, L, Orman, ES, Hagen, P-O, Amalfitano, A, Brian, L, and Freedman, NJ. "Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms." Cardiovascular Research 65.3 (February 2005): 674-682. Full Text
  - Zhang, L, Peppel, K, Brian, L, Chien, L, and Freedman, NJ. "Vein graft neointimal hyperplasia is exacerbated by tumor necrosis factor receptor-1 signaling in graft-intrinsic cells." Arteriosclerosis, Thrombosis, and Vascular Biology 24.12 (December 2004): 2277-2283. Full Text
  - Hildreth, KL, Wu, J-H, Barak, LS, Exum, ST, Kim, LK, Peppel, K, and 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." The Journal of Biological Chemistry 279.40 (October 2004): 41775-41782. Full Text
  - Freedman, NJ, and Lefkowitz, RJ. "Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation." The Journal of Clinical Investigation 113.10 (May 2004): 1379-1382. (Review) Full Text Open Access Copy
  - Zhang, L, Freedman, NJ, Brian, L, and Peppel, K. "Graft-extrinsic cells predominate in vein graft arterialization." Arteriosclerosis, Thrombosis, and Vascular Biology 24.3 (March 2004): 470-476. Full Text
  - Wu, J-H, Peppel, K, Nelson, CD, Lin, F-T, Kohout, TA, Miller, WE, Exum, ST, and Freedman, NJ. "The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor." The Journal of Biological Chemistry 278.45 (November 2003): 44238-44245. Full Text
  - Freedman, NJ, Kim, LK, Murray, JP, Exum, ST, Brian, L, Wu, J-H, and 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." The Journal of Biological Chemistry 277.50 (December 2002): 48261-48269. Full Text
  - Peppel, K, Zhang, L, Huynh, TTT, Huang, X, Jacobson, A, Brian, L, Exum, ST, Hagen, P-O, and Freedman, NJ. "Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells reduces neointimal hyperplasia." Journal of Molecular and Cellular Cardiology 34.10 (October 2002): 1399-1409. Full Text
  - Zhang, L, Hagen, P-O, Kisslo, J, Peppel, K, and Freedman, NJ. "Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model." Journal of Vascular Surgery 36.4 (October 2002): 824-832. Full Text
  - Liang, M, Freedman, NJ, Theiss, CT, and Liggett, SB. "Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch." Biochemistry 40.49 (December 11, 2001): 15031-15037. Link to Item
  - Peppel, K, Jacobson, A, Huang, X, Murray, JP, Oppermann, M, and 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 102.7 (August 15, 2000): 793-799. Link to Item
  - Pitcher, JA, Freedman, NJ, and Lefkowitz, RJ. "G protein-coupled receptor kinases." Annual Review of Biochemistry 67 (January 1998): 653-692. (Review) Full Text
  - Freedman, NJ, Ament, AS, Oppermann, M, Stoffel, RH, Exum, ST, and Lefkowitz, RJ. "Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity." The Journal of Biological Chemistry 272.28 (July 1997): 17734-17743. Full Text
  - Oppermann, M, Diversé-Pierluissi, M, Drazner, MH, Dyer, SL, Freedman, NJ, Peppel, KC, and Lefkowitz, RJ. "Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases." Proc Natl Acad Sci U S A 93.15 (July 23, 1996): 7649-7654. Open Access Copy Link to Item
  - Oppermann, M, Freedman, NJ, Alexander, RW, and Lefkowitz, RJ. "Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C." The Journal of Biological Chemistry 271.22 (May 1996): 13266-13272. Full Text
  - Freedman, NJ, and Lefkowitz, RJ. "Desensitization of G protein-coupled receptors." Recent Progress in Hormone Research 51 (January 1996): 319-351. (Review)
  - Pei, G, Kieffer, BL, Lefkowitz, RJ, and Freedman, NJ. "Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C." Molecular Pharmacology 48.2 (August 1995): 173-177.
  - Freedman, NJ, Liggett, SB, Drachman, DE, Pei, G, Caron, MG, and Lefkowitz, RJ. "Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase." The Journal of Biological Chemistry 270.30 (July 1995): 17953-17961. Full Text
  - Barak, LS, Tiberi, M, Freedman, NJ, Kwatra, MM, Lefkowitz, RJ, and Caron, MG. "A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration." J Biol Chem 269.4 (January 28, 1994): 2790-2795. Link to Item
  - Ishii, K, Chen, J, Ishii, M, Koch, WJ, Freedman, NJ, Lefkowitz, RJ, and Coughlin, SR. "Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase: Functional specificity among G-protein coupled receptor kinases." Journal of Biological Chemistry 269.2 (1994): 1125-1130.
  - Freedman, SF, Freedman, NJ, Shields, MB, Lobaugh, B, Samsa, GP, Keates, EU, and Ollie, A. "Effects of ocular carteolol and timolol on plasma high-density lipoprotein cholesterol level." Am J Ophthalmol 116.5 (November 15, 1993): 600-611. Link to Item
  - Inglese, J, Freedman, NJ, Koch, WJ, and Lefkowitz, RJ. "Structure and mechanism of the G protein-coupled receptor kinases." The Journal of Biological Chemistry 268.32 (November 1993): 23735-23738. (Review)
  - Liggett, SB, Freedman, NJ, Schwinn, DA, and Lefkowitz, RJ. "Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor." Proceedings of the National Academy of Sciences of the United States of America 90.8 (April 1993): 3665-3669. Full Text Open Access Copy
  - Resnick, D, Freedman, NJ, Xu, S, and Krieger, M. "Secreted extracellular domains of macrophage scavenger receptors form elongated trimers which specifically bind crocidolite asbestos." Journal of Biological Chemistry 268.5 (1993): 3538-3545.
  - Freeman, M, Ekkel, Y, Rohrer, L, Penman, M, Freedman, NJ, Chisolm, GM, and Krieger, M. "Expression of type I and type II bovine scavenger receptors in Chinese hamster ovary cells: Lipid droplet accumulation and nonreciprocal cross competition by acetylated and oxidized low density lipoprotein." Proceedings of the National Academy of Sciences of the United States of America 88.11 (1991): 4931-4935.
  - Penman, M, Lux, A, Freedman, NJ, Rohrer, L, Ekkel, Y, McKinstry, H, Resnick, D, and Krieger, M. "The type I and type II bovine scavenger receptors expressed in chinese hamster ovary cells are trimeric proteins with collagenous triple helical domains comprising noncovalently associated monomers and cys⁸³-disulfide-linked dimers." Journal of Biological Chemistry 266.35 (1991): 23985-23993.
  - Newrock, KM, Freedman, N, Alfageme, CR, and Cohen, LH. "Isolation of sea urchin embryo histone H2Aα1 and immunological identification of other stage-specific H2A proteins." Developmental Biology 89.1 (January 1982): 248-253. Full Text
Teaching & Mentoring
Recent Courses
- CELLBIO 493: Research Independent Study 2018
- CVS 301B: RESEARCH IN CVS 2018

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Education, Training, & Certifications

Duke Appointment History

Selected Grants

Selected Publications

Journal Articles

Recent Courses