Coronary artery disease, leading to myocardial infarction and ischemia, affects millions of people and is one of the leading causes of morbidity and mortality worldwide. Invasive techniques such as coronary artery bypass grafting (CABG) using the saphenous vein (SV) or internal mammary artery (IMA) are used to alleviate the sequelae of arterial occlusion. Unfortunately, restenosis, due to proliferation of vascular smooth muscle cells (VSMCs) in the grafted venous conduit, occurs within months to years with a gradual reduction in patency. Surprisingly, the IMA conduits are spared from the pathologic effects of fibroproliferation. However, the underlying cellular and molecular mechanisms, which are the basis for this difference, are unclear. Mechanical forces play an important role in the pathogenesis of vein graft disease. Alterations in shear stress result in the release of vasoactive mediators and modulate gene expression in VSMCs. Recently, we observed temporal inactivation of PTEN, a multifunctional lipid phosphatase, causing proliferation of SV SMCs, and that PTEN overexpression decreased IGF-1 receptors and cell proliferation. We also found that increased connexin43 (Cx43) expression following stimulation of SMCs with angiotensin II (Ang II) and IGF-1 significantly increases proliferation in the SMCs of SV than in the IMA. Since PTEN modulates cell signaling and cell growth, and communication between cells involving Cx43 plays a crucial role in the development of intimal hyperplasia, investigation of the regulatory role of PTEN in Cx43 expression and IGF-1 and Ang II- activated signaling, along with associated pro-hyperplasia pathways is now proposed. The central hypothesis is that PTEN decreases IGF-1 receptors in a feedback manner to regulate angiotensin II-IGF-1- induced proliferation and survival of smooth muscle cells from human CABG conduits by controlling PI3K-Akt/PKB pro-hyperplasia pathway and MAPK-AP-1-Cx43 expression.
AIM 1 : To examine the feedback effect of PTEN on IGF-1- and Ang-II-induced IGF-1 receptor expression and activation of the PI3K-Akt/PKB and MAPK pathways in SMCs of human SV and IMA and on the resultant proliferation.
AIM 2 : To investigate the effect of PTEN overexpression on the expression and activation of MAPK-AP-1-Cx43 in IGF-1- and Ang-II-stimulated SMCs of human SV and IMA, and on the resultant proliferation.
AIM 3 : To examine the effect of PTEN overexpression on Ang-II and IGF-1-induced expression and activation of cyclin- dependent kinase inhibitors (CKIs;p21, p27, and p53), cyclin D and E, Rb protein and E2F in SMCs of human SV and IMA, and on the resultant proliferation. The comparison of the precise mechanisms involved in the development of hyperplasia in SV and IMA bypass grafts should provide an opportunity to formulate superior therapeutic strategies.
Long term outcome of coronary artery bypass surgeries is compromised by re-closure of the vessels, which predominantly occurs in saphenous vein grafts while the internal mammary artery remains almost resistant to re-closure. In this project experiments are proposed to examine the underlying precise mechanisms at the cellular and molecular level. The information obtained from this study should provide an opportunity to formulate superior therapeutic approaches.
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