Scholars@Duke

• 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
• 

  Previous Appointments & Affiliations

  • 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

  • Mechanisms by which Small Nucleolar RNAs Exacerbate Atherosclerosis awarded by National Institutes of Health 2022 - 2026
  • Mechanisms Regulating Vascular Homeostasis awarded by National Institutes of Health 2021 - 2025
  • Anti-Atherogenic Mechanisms of Drebrin awarded by National Institutes of Health 2019 - 2023
  • Multidisciplinary Heart and Vascular Diseases awarded by National Institutes of Health 1975 - 2023
  • Regulation of Vascular Inflammatory Signaling by the Deubiquitinase USP20 awarded by National Institutes of Health 2019 - 2023
  • Mechanistic studies of Mas receptor activation and its role in aortic aneurysm formation awarded by National Institutes of Health 2017 - 2021
  • Role of Debrin in Vascular Smooth Muscle Transdifferentiation awarded by  American Heart Association 2019
  • 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
  • Same 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
• 

  External Relationships

  • Faiella & Gulden, P.A.
• Publications & Artistic Works
• 

  Selected Publications

  • Academic Articles

    • Freedman, Neil J. “From Colon to Aortic Aneurysm: Trek of the Treg.” Jacc Basic Transl Sci, vol. 7, no. 9, Sept. 2022, pp. 948–50. Pubmed, doi:10.1016/j.jacbts.2022.07.003.
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    • Wu, Jiao-Hui, et al. “Drebrin attenuates atherosclerosis by limiting smooth muscle cell transdifferentiation.” Cardiovasc Res, vol. 118, no. 3, Feb. 2022, pp. 772–84. Pubmed, doi:10.1093/cvr/cvab156.
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    • Zhang, Lisheng, et al. “Drebrin regulates angiotensin II-induced aortic remodelling.” Cardiovasc Res, vol. 114, no. 13, Nov. 2018, pp. 1806–15. Pubmed, doi:10.1093/cvr/cvy151.
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    • Jean-Charles, Pierre-Yves, et al. “USP20 (Ubiquitin-Specific Protease 20) Inhibits TNF (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates Atherosclerosis.” Arterioscler Thromb Vasc Biol, vol. 38, no. 10, Oct. 2018, pp. 2295–305. Pubmed, doi:10.1161/ATVBAHA.118.311071.
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    • Freedman, Neil J., and Sudha K. Shenoy. “Regulation of inflammation by β-arrestins: Not just receptor tales.” Cell Signal, vol. 41, Jan. 2018, pp. 41–45. Pubmed, doi:10.1016/j.cellsig.2017.02.008.
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    • Zhang, Lisheng, et al. “Interleukin-9 mediates chronic kidney disease-dependent vein graft disease: a role for mast cells.” Cardiovasc Res, vol. 113, no. 13, Nov. 2017, pp. 1551–59. Pubmed, doi:10.1093/cvr/cvx177.
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    • Smith, Jeffrey S., et al. “C-X-C Motif Chemokine Receptor 3 Splice Variants Differentially Activate Beta-Arrestins to Regulate Downstream Signaling Pathways.” Mol Pharmacol, vol. 92, no. 2, Aug. 2017, pp. 136–50. Pubmed, doi:10.1124/mol.117.108522.
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    • Stiber, Jonathan A., et al. “The Actin-Binding Protein Drebrin Inhibits Neointimal Hyperplasia.” Arterioscler Thromb Vasc Biol, vol. 36, no. 5, May 2016, pp. 984–93. Pubmed, doi:10.1161/ATVBAHA.115.306140.
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    • Jean-Charles, Pierre-Yves, et al. “Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of β-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor κB (NFκB) Activation.” J Biol Chem, vol. 291, no. 14, Apr. 2016, pp. 7450–64. Pubmed, doi:10.1074/jbc.M115.687129.
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    • Jean-Charles, P. .. Y., et al. “Chapter Nine - Cellular Roles of Beta-Arrestins as Substrates and Adaptors of Ubiquitination and Deubiquitination.” Prog Mol Biol Transl Sci, vol. 141, 2016, pp. 339–69. Pubmed, doi:10.1016/bs.pmbts.2016.04.003.
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    • Lu, Yuan, et al. “Kruppel-like factor 15 is critical for vascular inflammation.” J Clin Invest, vol. 123, no. 10, Oct. 2013, pp. 4232–41. Pubmed, doi:10.1172/JCI68552.
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    • Chandra, Rashmi, et al. “Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion.” J Clin Invest, vol. 123, no. 8, Aug. 2013, pp. 3343–52. Pubmed, doi:10.1172/JCI68587.
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    • Wu, Jiao-Hui, et al. “Kalirin promotes neointimal hyperplasia by activating Rac in smooth muscle cells.” Arterioscler Thromb Vasc Biol, vol. 33, no. 4, Apr. 2013, pp. 702–08. Pubmed, doi:10.1161/ATVBAHA.112.300234.
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    • Han, Sang-oh, et al. “MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors.” J Cell Biol, vol. 199, no. 5, Nov. 2012, pp. 817–30. Pubmed, doi:10.1083/jcb.201208192.
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    • Zhang, Lisheng, et al. “Vein graft neointimal hyperplasia is exacerbated by CXCR4 signaling in vein graft-extrinsic cells.” J Vasc Surg, vol. 56, no. 5, Nov. 2012, pp. 1390–97. Pubmed, doi:10.1016/j.jvs.2012.03.254.
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    • Wu, Jiao-Hui, et al. “G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors.” Arterioscler Thromb Vasc Biol, vol. 32, no. 2, Feb. 2012, pp. 308–16. Pubmed, doi:10.1161/ATVBAHA.111.239608.
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    • Brown, Melissa A., et al. “Human umbilical cord blood-derived endothelial cells reendothelialize vein grafts and prevent thrombosis.” Arterioscler Thromb Vasc Biol, vol. 30, no. 11, Nov. 2010, pp. 2150–55. Pubmed, doi:10.1161/ATVBAHA.110.207076.
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    • Zhu, Shoukang, et al. “Human umbilical cord blood endothelial progenitor cells decrease vein graft neointimal hyperplasia in SCID mice.” Atherosclerosis, vol. 212, no. 1, Sept. 2010, pp. 63–69. Pubmed, doi:10.1016/j.atherosclerosis.2010.04.018.
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    • Zhang, Lisheng, et al. “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, vol. 19, no. 14, July 2010, pp. 2754–66. Pubmed, doi:10.1093/hmg/ddq172.
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    • Cai, Xinjiang, et al. “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, vol. 75, no. 3, Mar. 2009, pp. 626–36. Pubmed, doi:10.1124/mol.108.050278.
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    • Shah, Svati H., et al. “Neuropeptide Y gene polymorphisms confer risk of early-onset atherosclerosis.” Plos Genet, vol. 5, no. 1, Jan. 2009, p. e1000318. Pubmed, doi:10.1371/journal.pgen.1000318.
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    • Shenoy, Sudha K., et al. “Nedd4 mediates agonist-dependent ubiquitination, lysosomal targeting, and degradation of the beta2-adrenergic receptor.” J Biol Chem, vol. 283, no. 32, Aug. 2008, pp. 22166–76. Pubmed, doi:10.1074/jbc.M709668200.
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    • Kim, Jihee, et al. “Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration.” Circ Res, vol. 103, no. 1, July 2008, pp. 70–79. Pubmed, doi:10.1161/CIRCRESAHA.108.172338.
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    • Wang, L., et al. “Polymorphisms of the tumor suppressor gene LSAMP are associated with left main coronary artery disease.” Ann Hum Genet, vol. 72, no. Pt 4, July 2008, pp. 443–53. Pubmed, doi:10.1111/j.1469-1809.2008.00433.x.
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    • Zhang, Lisheng, et al. “Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery.” Arterioscler Thromb Vasc Biol, vol. 28, no. 2, Feb. 2008, pp. 284–89. Pubmed, doi:10.1161/ATVBAHA.107.151613.
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    • Vinge, Leif Erik, et al. “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, vol. 72, no. 3, Sept. 2007, pp. 582–91. Pubmed, doi:10.1124/mol.107.035766.
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    • Zhang, Lisheng, et al. “Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis.” Arterioscler Thromb Vasc Biol, vol. 27, no. 5, May 2007, pp. 1087–94. Pubmed, doi:10.1161/ATVBAHA.0000261548.49790.63.
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    • Wu, Jiao-Hui, et al. “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, vol. 281, no. 49, Dec. 2006, pp. 37758–72. Pubmed, doi:10.1074/jbc.M605756200.
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    • Freedman, Neil J., and Geoffrey S. Ginsburg. “Novel--and "neu"--therapeutic possibilities for heart failure.” J Am Coll Cardiol, vol. 48, no. 7, Oct. 2006, pp. 1448–50. Pubmed, doi:10.1016/j.jacc.2006.07.005.
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    • Cai, Xinjiang, and Neil J. Freedman. “New therapeutic possibilities for vein graft disease in the post-edifoligide era.” Future Cardiol, vol. 2, no. 4, July 2006, pp. 493–501. Pubmed, doi:10.2217/14796678.2.4.493.
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    • Wu, Jiao-Hui, et al. “The platelet-derived growth factor receptor-beta phosphorylates and activates G protein-coupled receptor kinase-2. A mechanism for feedback inhibition.” J Biol Chem, vol. 280, no. 35, Sept. 2005, pp. 31027–35. Pubmed, doi:10.1074/jbc.M501473200.
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    • Peppel, Karsten, et al. “Activation of vascular smooth muscle cells by TNF and PDGF: overlapping and complementary signal transduction mechanisms.” Cardiovasc Res, vol. 65, no. 3, Feb. 2005, pp. 674–82. Pubmed, doi:10.1016/j.cardiores.2004.10.031.
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    • Zhang, Lisheng, et al. “Vein graft neointimal hyperplasia is exacerbated by tumor necrosis factor receptor-1 signaling in graft-intrinsic cells.” Arterioscler Thromb Vasc Biol, vol. 24, no. 12, Dec. 2004, pp. 2277–83. Pubmed, doi:10.1161/01.ATV.0000147766.68987.0d.
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    • Hildreth, Kerry L., et al. “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, vol. 279, no. 40, Oct. 2004, pp. 41775–82. Pubmed, doi:10.1074/jbc.M403274200.
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    • Freedman, Neil J., and Robert J. Lefkowitz. “Anti-beta(1)-adrenergic receptor antibodies and heart failure: causation, not just correlation.” J Clin Invest, vol. 113, no. 10, May 2004, pp. 1379–82. Pubmed, doi:10.1172/JCI21748.
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    • Zhang, Lisheng, et al. “Graft-extrinsic cells predominate in vein graft arterialization.” Arterioscler Thromb Vasc Biol, vol. 24, no. 3, Mar. 2004, pp. 470–76. Pubmed, doi:10.1161/01.ATV.0000116865.98067.31.
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    • Wu, Jiao-Hui, et al. “The adaptor protein beta-arrestin2 enhances endocytosis of the low density lipoprotein receptor.” J Biol Chem, vol. 278, no. 45, Nov. 2003, pp. 44238–45. Pubmed, doi:10.1074/jbc.M309450200.
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    • Freedman, Neil J., et al. “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, vol. 277, no. 50, Dec. 2002, pp. 48261–69. Pubmed, doi:10.1074/jbc.M204431200.
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    • Peppel, Karsten, et al. “Overexpression of G protein-coupled receptor kinase-2 in smooth muscle cells reduces neointimal hyperplasia.” J Mol Cell Cardiol, vol. 34, no. 10, Oct. 2002, pp. 1399–409. Pubmed, doi:10.1006/jmcc.2002.2092.
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    • Zhang, Lisheng, et al. “Neointimal hyperplasia rapidly reaches steady state in a novel murine vein graft model.” J Vasc Surg, vol. 36, no. 4, Oct. 2002, pp. 824–32.
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    • Liang, M., et al. “Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch.” Biochemistry, vol. 40, no. 49, Dec. 2001, pp. 15031–37. Pubmed, doi:10.1021/bi011453z.
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    • Peppel, K., et al. “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, vol. 102, no. 7, Aug. 2000, pp. 793–99. Pubmed, doi:10.1161/01.cir.102.7.793.
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    • Pitcher, J. A., et al. “G protein-coupled receptor kinases.” Annu Rev Biochem, vol. 67, 1998, pp. 653–92. Pubmed, doi:10.1146/annurev.biochem.67.1.653.
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    • Freedman, N. J., et al. “Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity.” J Biol Chem, vol. 272, no. 28, July 1997, pp. 17734–43. Pubmed, doi:10.1074/jbc.272.28.17734.
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    • Oppermann, M., et al. “Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases.” Proc Natl Acad Sci U S A, vol. 93, no. 15, July 1996, pp. 7649–54. Pubmed, doi:10.1073/pnas.93.15.7649.
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    • Oppermann, M., et al. “Phosphorylation of the type 1A angiotensin II receptor by G protein-coupled receptor kinases and protein kinase C.” J Biol Chem, vol. 271, no. 22, May 1996, pp. 13266–72. Pubmed, doi:10.1074/jbc.271.22.13266.
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    • Freedman, N. J., and R. J. Lefkowitz. “Desensitization of G protein-coupled receptors.” Recent Prog Horm Res, vol. 51, 1996, pp. 319–51.
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    • Pei, G., et al. “Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C.” Mol Pharmacol, vol. 48, no. 2, Aug. 1995, pp. 173–77.
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    • Freedman, N. J., et al. “Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase.” J Biol Chem, vol. 270, no. 30, July 1995, pp. 17953–61. Pubmed, doi:10.1074/jbc.270.30.17953.
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    • Barak, L. S., et al. “A highly conserved tyrosine residue in G protein-coupled receptors is required for agonist-mediated beta 2-adrenergic receptor sequestration.” J Biol Chem, vol. 269, no. 4, Jan. 1994, pp. 2790–95.
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    • Ishii, K., et al. “Inhibition of thrombin receptor signaling by a G-protein coupled receptor kinase. Functional specificity among G-protein coupled receptor kinases.” J Biol Chem, vol. 269, no. 2, Jan. 1994, pp. 1125–30.
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    • Inglese, J., et al. “Structure and mechanism of the G protein-coupled receptor kinases.” J Biol Chem, vol. 268, no. 32, Nov. 1993, pp. 23735–38.
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    • Freedman, S. F., et al. “Effects of ocular carteolol and timolol on plasma high-density lipoprotein cholesterol level.” Am J Ophthalmol, vol. 116, no. 5, Nov. 1993, pp. 600–11. Pubmed, doi:10.1016/s0002-9394(14)73203-9.
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    • Liggett, S. B., et al. “Structural basis for receptor subtype-specific regulation revealed by a chimeric beta 3/beta 2-adrenergic receptor.” Proc Natl Acad Sci U S A, vol. 90, no. 8, Apr. 1993, pp. 3665–69. Pubmed, doi:10.1073/pnas.90.8.3665.
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    • Resnick, D., et al. “Secreted extracellular domains of macrophage scavenger receptors form elongated trimers which specifically bind crocidolite asbestos.” J Biol Chem, vol. 268, no. 5, Feb. 1993, pp. 3538–45.
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    • Penman, M., et al. “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.” J Biol Chem, vol. 266, no. 35, Dec. 1991, pp. 23985–93.
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    • Freeman, M., et al. “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.” Proc Natl Acad Sci U S A, vol. 88, no. 11, June 1991, pp. 4931–35. Pubmed, doi:10.1073/pnas.88.11.4931.
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    • Newrock, Kenneth M., et al. “Isolation of sea urchin embryo histone H2Aα1 and immunological identification of other stage-specific H2A proteins.” Developmental Biology, vol. 89, no. 1, Elsevier BV, Jan. 1982, pp. 248–53. Crossref, doi:10.1016/0012-1606(82)90311-6.
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• Teaching & Mentoring
• 

  Recent Courses

  • CELLBIO 493: Research Independent Study 2023
  • CVS 301B: RESEARCH IN CVS 2023
  • CELLBIO 493: Research Independent Study 2022
  • CVS 301B: RESEARCH IN CVS 2022
  • CELLBIO 493: Research Independent Study 2021
  • CVS 301B: RESEARCH IN CVS 2021

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