Intimal hyperplasia and restenosis following interventional procedures remain significant clinical problems. Drug-eluting stents cause less intimal hyperplasia and less late luminal loss, but inhibit re- endothelialization of the stented segment making it more susceptible to thrombosis requiring longer periods of anti-platelet therapy. Clearly, an additional therapeutic approach would be useful to prevent intimal hyperplasia and provide long-term symptom-free control of coronary artery disease. SOCS3 regulates the activity of mitogens in VSMCs, and in the presence of both mitogen and inflammatory cytokines, the SOCS3 gene is silenced, leading to increased proliferative effect of growth factors. This justifies the introduction of the SOCS3 gene in coronary arteries as a viable approach to control intimal hyperplasia. The hypothesis is that delivery of the SOCS3 transgene locally to the site of angioplasty and stent injury prevents the development of neointimal hyperplasia and in-stent restenosis which is due to silencing of the SOCS3 gene by hypermethylation and enhanced STAT3 and NF-kB transcriptional activity in coronary artery smooth muscle cells. We propose to utilize hyperlipidemic and atherosclerotic microswine model with angioplasty and in-stent restenosis.
Aim 1 : Our hypothesis predicts that the introduction of SOCS3 transgene at the site of balloon angioplasty in atherosclerotic coronary artery will prevent the development of intimal hyperplasia.
Aim 2 : Our hypothesis predicts that the introduction of SOCS3 transgene at the site of bare metal stenting in atherosclerotic coronary artery will prevent in-stent restenosis and this would be superior to the effect of drug- eluting stent alone. In both these aims, AAV9-mediated gene transfer will be used to overexpress SOCS3 in VSMCs at the site of interventional procedure in coronary arteries of hyperlipidemic and atherosclerotic microswine. Clinical and histological parameters of intimal hyperplasia and in-stent restenosis in coronary arteries will be examined.
Aim 3 : Our hypothesis predicts that the intimal hyperplasia following balloon angioplasty and intravascular stenting is due to silencing of SOCS3 promoter by hypermethylation and enhanced transcriptional activity of STAT3 and NF-kB in coronary artery smooth muscle cells and that restoration of SOCS3 by gene therapy results in down-regulation of active NF-kB and STAT3, induction of apoptosis and growth suppression of VSMCs. We will determine whether or not aberrant hypermethylation of promoter regions in CpG islands is associated with transcriptional silencing of the SOCS3 gene and up- regulation of active NF-kB and STAT3 in SMCs of neointimal lesions in coronary artery following balloon angioplasty and with in-stent stenosis, whether or not this is suppressed by SOCS3 gene therapy. These studies will provide the conceptual support of our hypothesis and position us to translate our investigation into a clinical phase 1 study for the gene delivery of SOCS3 in patients with coronary artery disease.

Public Health Relevance

Re-narrowing of coronary arteries in the heart after balloon angioplasty or placement of stents is serious problem. This is primarily due to uncontrolled growth of smooth muscle cells at the site of injury due to balloon angioplasty or the placement of stent in coronary artery. In this project we proposed to deliver a novel gene at the site of injury in the heart of atherosclerotic pig during these procedures to prevent the re-narrowing of the coronary arteries and keep them patent for longer period. The goal is to test the hypothesis that SOCS3 gene therapy is superior to drug-eluting stents. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical phase 1 study for the gene delivery in patients with coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL104516-03
Application #
8452694
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Fleg, Jerome
Project Start
2011-04-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$587,008
Indirect Cost
$180,774
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Pelham, Christopher J; Drews, Elizabeth M; Agrawal, Devendra K (2016) Vitamin D controls resistance artery function through regulation of perivascular adipose tissue hypoxia and inflammation. J Mol Cell Cardiol 98:1-10
Sur, Swastika; Swier, Vicki J; Radwan, Mohamed M et al. (2016) Increased Expression of Phosphorylated Polo-Like Kinase 1 and Histone in Bypass Vein Graft and Coronary Arteries following Angioplasty. PLoS One 11:e0147937
Swier, Vicki J; Tang, Lin; Radwan, Mohamed M et al. (2016) The role of high cholesterol-high fructose diet on coronary arteriosclerosis. Histol Histopathol 31:167-76
Kokubun, Kelsey; Pankajakshan, Divya; Kim, Min-Jung et al. (2016) Differentiation of porcine mesenchymal stem cells into epithelial cells as a potential therapeutic application to facilitate epithelial regeneration. J Tissue Eng Regen Med 10:E73-83
Lee, Dylan E; Ayoub, Nagi; Agrawal, Devendra K (2016) Mesenchymal stem cells and cutaneous wound healing: novel methods to increase cell delivery and therapeutic efficacy. Stem Cell Res Ther 7:37
Nguyen, Austin H; Miller, Elliott J; Wichman, Christopher S et al. (2015) Diagnostic value of tumor antigens in malignant pleural effusion: a meta-analysis. Transl Res 166:432-9
Swier, Vicki J; Tang, Lin; Krueger, Kristopher D et al. (2015) Coronary Injury Score Correlates with Proliferating Cells and Alpha-Smooth Muscle Actin Expression in Stented Porcine Coronary Arteries. PLoS One 10:e0138539
Boosani, Chandra S; Dhar, Kajari; Agrawal, Devendra K (2015) Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3. Mol Biol Rep 42:1365-76
Thompson, David B; Siref, Larry E; Feloney, Michael P et al. (2015) Immunological basis in the pathogenesis and treatment of bladder cancer. Expert Rev Clin Immunol 11:265-79
Nguyen, Austin Huy; Koenck, Carleigh; Quirk, Shannon K et al. (2015) Triggering Receptor Expressed on Myeloid Cells in Cutaneous Melanoma. Clin Transl Sci 8:441-4

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