Aortocoronary vein graft atherosclerosis afflicts over two million Americans. While it shares many features with atherosclerosis of native arteries, vein graft atherosclerosis progresses considerably more rapidly. Inasmuch as atherosclerosis is a chronic inflammatory disorder, inflammatory cytokines such as Tumor Necrosis Factor alpha (TNFalpha) might contribute to vascular lesion development. Preliminary studies demonstrate a strong proatherogenic activity of TNF on vascular smooth muscle cells (SMCs) in vitro. Our Central Hypothesis is that TNF contributes substantially to vein graft failure in vivo. While both activated macrophages and SMCs can produce TNF, the contribution of this cytokine to vein graft disease, and the cellular and molecular mechanisms by which TNF may accentuate vein graft atherosclerosis, are incompletely understood. To study these issues, we recently developed a new murine vein graft model that uses congenic inferior vena cavae to carotid artery interposition grafts. As a result, we can manipulate the genetic background of the vein graft wall independently from that of the recipient's circulating cells. Our preliminary studies show a significant reduction (40%) of vein graft neointima formation in grafts that are deficient in TNF receptor 1 signaling (TNFR1-/-), when placed into normolipidemic TNFR1-/- recipients.
Our first aim i s to determine the role of TNFalpha in vein graft atherosclerosis under normal and hyperlipidemic conditions in vivo. To achieve this aim, we will use wild type (C57Bl/6) or congenic apolipoprotein E deficient (ApoE-/-) mice as pro-atherogenic recipients of congenic vein grafts. The vein grafts will be derived from either wild type or TNF receptor-1-deficient (TNFR1-/-) mice. All of the recipient mice will also express the beta-galactosidase marker gene (from the Rosa 26 mouse strain) to allow for evaluation of vein graft infiltration by recipient-derived cells.
Our second aim i s to assess the potential for a recombinant TNF Inhibitor to attenuate vein graft neointima formation in mice with normal or elevated lipid levels. This will be achieved by examining vein graft remodeling in wild-type or ApoE-/- mice, that have been infected with a recombinant adenovirus expressing a p55TNFR1-IgG fusion protein that we have created. Defining cellular mechanisms by which TNF promotes vein graft atherosclerosis may have therapeutic implications for the many patients with vein graft disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072842-03
Application #
7079259
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Ershow, Abby
Project Start
2004-07-01
Project End
2006-12-31
Budget Start
2006-06-01
Budget End
2006-12-31
Support Year
3
Fiscal Year
2006
Total Cost
$9,842
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Sen, Anagha; Most, Patrick; Peppel, Karsten (2014) Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction. FEBS Lett 588:906-14
Wu, Jiao-Hui; Zhang, Lisheng; Fanaroff, Alexander C et al. (2012) G protein-coupled receptor kinase-5 attenuates atherosclerosis by regulating receptor tyrosine kinases and 7-transmembrane receptors. Arterioscler Thromb Vasc Biol 32:308-16
Zhang, Lisheng; Connelly, Jessica J; Peppel, Karsten et al. (2010) 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 19:2754-66
Kim, Jihee; Zhang, Lisheng; Peppel, Karsten et al. (2008) Beta-arrestins regulate atherosclerosis and neointimal hyperplasia by controlling smooth muscle cell proliferation and migration. Circ Res 103:70-9
Zhang, Lisheng; Sivashanmugam, Perumal; Wu, Jiao-Hui et al. (2008) Tumor necrosis factor receptor-2 signaling attenuates vein graft neointima formation by promoting endothelial recovery. Arterioscler Thromb Vasc Biol 28:284-9
Zhang, Lisheng; Peppel, Karsten; Sivashanmugam, Perumal et al. (2007) Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis. Arterioscler Thromb Vasc Biol 27:1087-94
Reutershan, Jorg; Stockton, Rebecca; Zarbock, Alexander et al. (2007) Blocking p21-activated kinase reduces lipopolysaccharide-induced acute lung injury by preventing polymorphonuclear leukocyte infiltration. Am J Respir Crit Care Med 175:1027-35