While percutaneous delivery of endovascular stents has been shown to reduce the frequency, restenosis still complicates 22-28% of stented coronary arteries despite advances in stent deployment techniques. Neointimal thickening has been inferred to result most often from vascular smooth muscle cell (SMC) proliferation. Strategies targeting this phenomenon have reduced the incidence of restenosis, however there also appears to be evidence for impaired endothelial recovery associated with brachytherapy and perhaps antiproliferative drug eluting stents. Previous studies carded out in a variety of animal species have repeatedly shown that extensive endothelial denudation of the artery wall promotes neointimal thickening. We have therefore considered the possibility that those stents which develop refractory intimal thickening, as well as a portion of restenosis lesions which originate in non-stented arteries or bypass grafts post-PTCA, may result in part from belated endothelial recovery. We have now developed substantial evidence that tumor necrosis factor alpha (TNF), which is expressed at sites of balloon injury, can impair endothelial recovery by inhibiting the proliferation of endothelial cells adjacent to the site of injury. Our studies also show that endothelial recovery can be improved by blocking TNF's effects. Recently we have discovered that TNF activates a novel transcription factor function of Ezrin, formerly thought to be a cytoskeletal protein, which results in the inhibition of certain cell cycle promoters. We have found that TNF specifically inhibits the activity of another transcription factor, E2F1, which normally promotes proliferation. Finally, we have evidence that circulating, bone marrow derived endothelial progenitor cells contribute to the recovery of the endothelium at sites of injury and that TNF also inhibits the proliferation of these cells.
In Specific Aim 1 we will investigate the mechanisms by which Ezrin inhibits EC proliferation and determine if inhibition of Ezrin activity can result in improved endothelial recovery in vivo.
In Specific Aim 2 we will investigate the effect of Ezrin on bone marrow derived endothelial progenitor cells and determine the impact on re-endothelializaiton.
In Specific Aim 3 we will investigate mechanisms responsible for repression of E2F1 activity and evaluate the effect of inhibition of this effect on ReEndo. Together these studies will result in a better understanding of the mechanisms, which govern EC recovery at sites of balloon injury and may lead to novel therapeutic strategies targeting endothelial recovery. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063414-07
Application #
7026006
Study Section
Pathology A Study Section (PTHA)
Program Officer
Sopko, George
Project Start
1999-08-15
Project End
2006-12-31
Budget Start
2006-04-01
Budget End
2006-12-31
Support Year
7
Fiscal Year
2006
Total Cost
$384,794
Indirect Cost
Name
St. Elizabeth's Medical Center of Boston
Department
Type
DUNS #
073797292
City
Boston
State
MA
Country
United States
Zip Code
01235
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