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. Thus, there is trade-off between restenosis and late stent thrombosis requiring longer periods of anti-platelet therapy. Clearly, a better therapeutic approach that can prevent intimal hyperplasia and induce re-endothelialization would be useful to provide long-term symptom-free control of coronary artery disease without the need for prolonged anti- platelet therapy. Since PTEN modulates cell signaling and cell growth, PTEN transgene overexpression in arterial smooth muscle cells would prevent the development of neointimal hyperplasia. In addition, thrombosis could be prevented by the repair of endothelial cells with mesenchymal stem cells (MSCs) which have been primed to differentiate into endothelial cells. We hypothesize that the delivery of MSCs and PTEN transgene locally to the site of angioplasty and stent injury prevents thrombosis and the development of neointimal hyperplasia. Down-regulation of Wnt/2 catenin signaling in MSCs promotes endothelial cell differentiation and re-endothelialization. This hypothesis has been supported by our data demonstrating that vascular endothelial growth factor (VGEF)-primed MSCs differentiate into endothelial cells and PTEN overexpression inhibits proliferation of arterial smooth muscle cells. We will do these studies in a well-established and routinely used in our laboratory the swine model of hyperlipidemia and atherosclerosis with angioplasty and in-stent restenosis.
Aim 1 : Test the hypothesis that overexpression of PTEN transgene with MSCs at the site of balloon angioplasty in atherosclerotic coronary artery prevents thrombosis and the development of neointimal hyperplasia.
Aim 2 : Test the hypothesis that overexpression of PTEN transgene with MSCs at the site of bare metal stenting in atherosclerotic coronary artery prevents thrombosis and in-stent restenosis and this would be superior to the effect of drug-eluting stent alone.
Aim 3 : Test the hypothesis that down-regulation of Wnt/2-catenin signaling promotes MSC differentiation to endothelial cells at the injury site in coronary arteries. We will examine the role of Wnt/?-catenin signaling molecules, particularly ?-catenin, LRP5 and Kremen1, as the underlying mechanism of MSCs differentiation into ECs and re-endothelialization both in vitro and in vivo in swine coronary arteries. These studies would position us to translate our investigation into a clinical phase 1 study for the use of PTEN-engineered autologous MSCs for the treatment of the complications due to coronary interventional procedures, and PTCA with PTEN-engineered autologous MSCs might eliminate the need of stents in 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. Another major problem is the deposition of platelets that develop thrombosis. In this project we proposed to deliver autologous mesenchymal stem cells together with 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 the administration of stem cells with 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 delivery of stem cells with the novel gene 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 #
5R01HL112597-03
Application #
8585877
Study Section
Special Emphasis Panel (ZRG1-VH-B (02))
Program Officer
Kindzelski, Andrei L
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
3
Fiscal Year
2014
Total Cost
$716,035
Indirect Cost
$217,142
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Thankam, Finosh G; Boosani, Chandra S; Dilisio, Matthew F et al. (2018) MicroRNAs associated with inflammation in shoulder tendinopathy and glenohumeral arthritis. Mol Cell Biochem 437:81-97
Agarwal, Shreya; Kovilam, Oormila; Agrawal, Devendra K (2018) Vitamin D and its impact on maternal-fetal outcomes in pregnancy: A critical review. Crit Rev Food Sci Nutr 58:755-769
Rosenberg, John H; Werner, John H; Moulton, Michael J et al. (2018) Current Modalities and Mechanisms Underlying Cardioprotection by Ischemic Conditioning. J Cardiovasc Transl Res 11:292-307
Werner, John H; Rosenberg, John H; Keeley, Kristen L et al. (2018) Immunobiology of periprosthetic inflammation and pain following ultra-high-molecular-weight-polyethylene wear debris in the lumbar spine. Expert Rev Clin Immunol 14:695-706
Ludwig, Parker E; Thankam, Finosh G; Patil, Arun A et al. (2018) Brain injury and neural stem cells. Neural Regen Res 13:7-18
Plitt, Gilman D; Spring, Jordan T; Moulton, Michael J et al. (2018) Mechanisms, diagnosis, and treatment of heart failure with preserved ejection fraction and diastolic dysfunction. Expert Rev Cardiovasc Ther 16:579-589
Rudick, Courtney P; Cornell, David L; Agrawal, Devendra K (2017) Single versus combined immunoregulatory approach using PD-1 and CTLA-4 modulators in controlling sepsis. Expert Rev Clin Immunol 13:907-919
Almalki, Sami G; Agrawal, Devendra K (2017) ERK signaling is required for VEGF-A/VEGFR2-induced differentiation of porcine adipose-derived mesenchymal stem cells into endothelial cells. Stem Cell Res Ther 8:113
Rai, Vikrant; Sharma, Poonam; Agrawal, Swati et al. (2017) Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research. Mol Cell Biochem 424:123-145
Rosenberg, John H; Rai, Vikrant; Dilisio, Matthew F et al. (2017) Damage-associated molecular patterns in the pathogenesis of osteoarthritis: potentially novel therapeutic targets. Mol Cell Biochem 434:171-179

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