Previous investigations by us and others have used a cell culture system to establish the vascular function of TN. We have now extended these observations in vivo to test the hypothesis that the genetic deletion of TN in the apo E-/- background might modify neointimal hyperplasia in an injured artery, and in atherosclerotic lesions. TN/E-mice developed atherosclerotic lesions one-week after being fed on a high fat diet. This lesion development was more rapid and more complex than was observed with Apo E mice. Concomitantly, VCAM- 1 expression was detected in the TN/E group alone. FACS analysis revealed that the VCAM-1 expression level in TN/E-derived endothelial cells was markedly higher than that from apo E mice. Finally, TN was found to down-regulate VCAM-1 promoter activity when induced by TNF-a in endothelial cells. These data suggest that TN deficiency promotes leukocyte/endothelial cell interaction. In addition to the rapid development of plaque, chronic hyperlipidemia in TN/E mice resulted in the formation of unstable plaques. The antibody array and ELISA analyses of chronic hyperlipidemic plasma from the two mouse genotypes showed that eotaxin, a CC chemokine, is selectively upregulated by 4- to 5-fold in the TN/E groups when compared to apo E mice. Furthermore, there was an accumulation of mast cells in the adventitia of unstable lesions in TN/E group. Collectively, our data point to an anti-inflammatory role for TN in vascular diseases. The overall goal of this proposal is to test 4 specific hypotheses (Aims). - Aim 1. A specific domain/segment of TN negatively regulates TNF-a induced VCAM-1 promoter activity.
Aim 2. Chronic hyperlipidemia in TN/E mice up-regulates eotaxin promoting an accumulation of mast cells.
Aim 3. TN deficiency promotes neointimal formation after vascular injury.
Aim 4. TN deficiency per se is sufficient for neointimal formation. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050566-10
Application #
7219492
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Sopko, George
Project Start
1995-06-01
Project End
2010-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
10
Fiscal Year
2007
Total Cost
$378,690
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Song, Lei; Wang, Lai; Li, Fuqiang et al. (2017) Bone Marrow-Derived Tenascin-C Attenuates Cardiac Hypertrophy by Controlling Inflammation. J Am Coll Cardiol 70:1601-1615
Wang, Lai; Shah, Prediman K; Wang, Wei et al. (2013) Tenascin-C deficiency in apo E-/- mouse increases eotaxin levels: implications for atherosclerosis. Atherosclerosis 227:267-74
Wang, Lai; Wang, Wei; Shah, Prediman K et al. (2012) Deletion of tenascin-C gene exacerbates atherosclerosis and induces intraplaque hemorrhage in Apo-E-deficient mice. Cardiovasc Pathol 21:398-413
Li, Fuqiang; Tian, Fang; Wang, Lai et al. (2010) Pleiotrophin (PTN) is expressed in vascularized human atherosclerotic plaques: IFN-{gamma}/JAK/STAT1 signaling is critical for the expression of PTN in macrophages. FASEB J 24:810-22
Song, Lei; Wang, Lai; Shah, Prediman K et al. (2010) Bioengineered vascular graft grown in the mouse peritoneal cavity. J Vasc Surg 52:994-1002, 1002.e1-2
Wang, Lai; Sharifi, Behrooz G; Pan, Theresa et al. (2006) Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice. J Am Coll Cardiol 48:1459-68
Sharifi, Behrooz G; Zeng, Zhaohui; Wang, Lai et al. (2006) Pleiotrophin induces transdifferentiation of monocytes into functional endothelial cells. Arterioscler Thromb Vasc Biol 26:1273-80