Saphenous vein (SV) graft failure is a common clinical problem in patients undergoing coronary artery bypass graft (CABG) surgery. Underlying mechanisms are still unclear. Failure of various therapies, including targeted gene therapy, could be due to the bad choice of the gene and/or the use of animal model dissimilar to human disease. Also, there was no consideration to promote endothelial cell proliferation. We observed inactivation of PTEN with increased proliferation of SMCs in human SV and PTEN overexpression limits cell proliferation. Since PTEN modulates cell signaling and cell growth, PTEN transgene expression in SV graft SMCs would prevent the development of intimal hyperplasia. Also, the repair of endothelial cells (ECs) with mesenchymal stem cells (MSCs) would inhibit thrombosis. The hypothesis is that the inhibition of intimal hyperplasia by PTEN transgene while preserving endothelium with the delivery of MSCs in autologous vein grafts prior to CABG would be the best strategy to maintain vein graft patency. We will do these studies in a well-established and routinely used in our laboratory the swine model of atherosclerosis and perform CABG using superficial epigastric vein (SEV) isolated with no touch technique.
Aim 1 : Our hypothesis predicts that the overexpression of PTEN transgene in the SMCs of vein graft in coronary arteries in atherosclerotic swine will prevent the development of neointimal hyperplasia in bypass vein graft.
Aim 2 : Our hypothesis predicts that the repair of endothelial cells with MSCs together with PTEN transgene in the SMCs of vein graft in coronary arteries of atherosclerotic swine will prevent thrombosis and neointimal hyperplasia in bypass vein graft, and this would be superior to the effect of PTEN transgene alone.
Aim 3 : Our hypothesis predicts that overexpression of PTEN transgene and MSCs-induced endothelial cell regeneration would reduce inflammation and inhibit constrictive remodeling together with inhibition of neointimal hyperplasia in the vein graft in coronary arteries. The autologous SEV will be exposed to PTEN vector and MSCs followed by aorto-coronary grafting in atherosclerotic swine. EKG and echocardiography to monitor heart function, and coronary angiography and optimal coherence tomography to quantify in-segment minimal luminal diameter, diameter stenosis, late loss and intimal hyperplasia will examine the therapeutic efficacy of this therapy. Histological parameters will include the intimal thickness, lumen area, intima-media ratio, development and ulceration of plaque, thrombosis, extracellular matrix, and re-occlusion. Expression of pro- and anti-inflammatory and pro-hyperplasia pathways will be examined in excised vein graft and correlated with the degree of neointimal hyperplasia and constrictive remodeling. Findings from these studies will provide the conceptual support for our hypothesis, and position us to translate our investigation into a clinical phase 1 study for the use of PTEN-engineered autologous MSCs for the treatment and possibly cure of the vein graft disease following CABG.

Public Health Relevance

Vein graft failure is a serious clinical problem with increase in morbidity and mortality following coronary artery bypass graft. Failure of the grafted saphenous vein is due to the re-closure of the grafted vessel in the heart that can occur within months or the first few years. Although the outcome results after grafting internal mammary artery are far better, it cannot be used in patients with history of radiation, aortic coarctation and other vascular problems. Also, artery cannot be grafted in all branches of the coronary system in the heart. In this study, we proposed novel mechanisms by transducing a gene and preserving endothelium in the grafted vein to maintain patency of the vein graft and determine underlying cellular and molecular mechanisms. The proposed studies will provide conceptual support of our hypothesis and position us to translate our investigation into a clinical study in patients wit coronary artery disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL128063-03
Application #
9234420
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lee, Albert
Project Start
2015-03-13
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Creighton University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
053309332
City
Omaha
State
NE
Country
United States
Zip Code
68178
Almalki, Sami G; Agrawal, Devendra K (2016) Key transcription factors in the differentiation of mesenchymal stem cells. Differentiation 92:41-51
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
Nandipati, Kalyana C; Subramanian, Saravanan; Agrawal, Devendra K (2016) Protein kinases: mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance. Mol Cell Biochem :
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
Smith, Tyler A; Kirkpatrick, Daniel R; Kovilam, Oormila et al. (2015) Immunomodulatory role of vitamin D in the pathogenesis of preeclampsia. Expert Rev Clin Immunol 11:1055-63
Ikhapoh, Izuagie Attairu; Pelham, Christopher J; Agrawal, Devendra K (2015) Sry-type HMG box 18 contributes to the differentiation of bone marrow-derived mesenchymal stem cells to endothelial cells. Differentiation 89:87-96
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