Abstract
Vascular restenosis is a common adverse event following percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). The atypical Ser/Thr protein kinase mammalian target of rapamycin (mTOR) plays an important role in cell differentiation and apoptosis. Vascular restenosis caused by excessive endothelial cell proliferation can be inhibited by local application of the mTOR inhibitor rapamycin (RAPA); however, RAPA can also suppress normal vascular endothelial cell growth by blocking mTOR/VEGF signaling, although the underlying mechanism is still unclear. Here, endogenous mTOR, AP-1, and VEGF were inhibited or overexpressed to investigate the mechanism underlying the effects of RAPA. Inhibition of AP-1 or mTOR with AP-1-siRNA or RAPA treatment respectively, decreased vascular endothelial cell proliferation, upregulation of AP-1 or mTOR increased cell proliferation, and VEGF overexpression increased, while RAPA-induced mTOR inhibition decreased vascular endothelial cell proliferation, the results indicate that combining mTOR downregulation and VEGF upregulation might both inhibit restenosis and maintain normal vascular endothelial cell growth after PCI or CABG, suggest the mTOR/AP-1/VEGF pathway might play a crucial role in regulating vascular endothelial cell growth.
Highlights
The incidence of human coronary heart disease (CHD) has recently been increasing year by year [1]
Mammalian target of rapamycin is an atypical Ser/Thr protein kinase that interacts with multiple growth factors and cytokines and participates in different signaling pathways to affect transcription and protein synthesis. mammalian target of rapamycin (mTOR), which is a downstream molecule of the PI3K/Akt/mTOR signaling pathway, is inhibited by rapamycin (RAPA)
Vascular restenosis resulting from percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG), as well as vascular endothelial cell growth, is inhibited by RAPA-induced mTOR suppression [11]
Summary
The incidence of human coronary heart disease (CHD) has recently been increasing year by year [1]. Rapamycin (RAPA), an inhibitor of mTOR, inhibits proliferation and migration and accelerates apoptosis in endothelial cells, and delays the formation of new intima on the surface of stents [6]. RAPA-eluting stents, which decrease the incidence of coronary restenosis [7], are widely used in the treatment of coronary artery disease. The highly-specific vascular endothelial growth factor (VEGF) promotes proliferation, angiogenesis, and extracellular matrix alterations and increases vascular permeability, and RAPA treatment downregulates VEGF expression in vascular endothelial cells [8]. The mechanisms by which mTOR in regulates VEGF expression in vascular endothelial cells is unclear. We explored the mechanism by which mTOR and the mTOR/AP-1/VEGF pathway regulates vascular endothelial cell proliferation
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