Background. Studies indicate the dramatic reduction of shear stress (SS) within the rapamycin eluting stent (RES) segment of coronary arteries. It remains unclear about the role of rapamycin in endothelialization of stented arteries where SS becomes low. Since mTOR (mammalian target of rapamycin) pathway is involved in the antioxidative sestrins expression, we hypothesized that rapamycin attenuated low SS (LSS) induced endothelial dysfunction through mTOR and sestrin1 associated redox regulation. Methods and Results. To mimic the effect of LSS on the stented arteries, a parallel plate flow chamber was used to observe the interplay of LSS and rapamycin on endothelial cells (ECs). The results showed LSS significantly induced EC apoptosis which was mitigated by pretreatment of rapamycin. Rapamycin attenuated LSS induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) production via prohibition of sestrin1 downregulation. Activities of mTORC1 and mTORC2 were detected contradictorily modulated by LSS. Inhibition of rictor expression by target small interfering RNA (siRNA) transfection prohibited sestrin1 downregulation induced by LSS, but inhibition of raptor did not. Conclusions. Rapamycin may prohibit sestrin1 downregulation through targeting mTORC2 in appeasing LSS induced EC oxidative apoptosis. Our results provide the in vitro evidence to explain the pathophysiology of RES stented arteries. 1. Introduction Rapamycin, the specific inhibitor of mTOR (mammalian target of rapamycin), is a natural product of the soil actinomycete streptomyces hygroscopicus [1]. Rapamycin and its derivatives are widely employed in the rapamycin eluting stent (RES) because they successfully prevent in-stent restenosis [2]. However, rapamycin is suspected to compromise endothelial function and induce endothelial apoptosis [3] and even implicate to delayed endothelialization [4–7]. Conversely, other researchers found rapamycin was not such cytotoxic to ECs as it arrested ECs at G0/G1 phase of cell cycle without inducing apoptosis [8]. Furthermore, rapamycin was reported to attenuate high-amplitude, mechanical stretch-induced apoptosis in pulmonary microvascular endothelial cells [9]. Therefore, the potential of rapamycin on EC apoptosis needs to be clarified. Low shear stress (LSS) is a well-established risk factor resulting in endothelial dysfunction and atherosclerotic lesions [10, 11]. Data from our previous in vivo studies demonstrated that SS on the luminal surface of stented coronary artery reduced dramatically after implantation of RES [12, 13]. In the
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