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  • The feasibility of using the Fas

    2022-03-30

    The feasibility of using the Fas/Fas ligand (FasL) system to target vascular progenitor 9620 receptor contributing to intimal hyperplasia has been shown in many studies [[18], [19], [20], [21], [22], [23], [24]]. Fas receptor, a member of tissue necrosis factor family, is a death receptor that initiates apoptosis upon activation by its ligand, FasL [18,19]. Ectopic and increased expression of FasL may be effective in inducing apoptosis in Fas-bearing vascular SMCs and macrophages [20,23,24]. ECs, however, are comparably resistant to Fas-mediated apoptosis, since they endogenously express surface FasL. One possible mechanism that protects ECs is that the Fas-mediated death signal is blocked by FLICE (Fas-associated death domain–like interleukin-1β–converting enzyme)-inhibitory proteins (FLIPs) [[25], [26], [27]]. Hence, the local delivery of FasL to sites of the injured vessel wall has the potential to decrease the number of SMCs without affecting re-endothelialization [20,25]. Interestingly, over-expression of FasL in ECs via adenovirus-mediated gene transfer decreases balloon injury-related intimal hyperplasia, by inducing apoptosis in SMCs or infiltrating host inflammatory cells, without self-destruction of the ECs expressing the FasL [[21], [22], [23],28]. Intriguingly, nitric oxide (NO) is known to increase surface Fas receptors on vascular SMCs [29,30]. NO from overexpression of inducible nitric oxide synthase (iNOS) results in pro-apoptotic p53 protein accumulation in human fibroblasts [31]. Furthermore, p53 induces surface Fas expression in VSMCs by translocation of a preformed pool from the Golgi apparatus [30,32]. Therefore, we hypothesize that local delivery of NO can be used to increase Fas receptor expression on the cell surface and enhance the potential anti-SMC therapeutic effect of FasL delivered to the same region (Fig. 1). Here, for the first time, we studied the effect of FasL and NO combination on SMCs and ECs. In addition, to demonstrate proof of concept, we showed the feasibility of releasing the FasL and NO combinations from a stent surface to control SMC proliferation/apoptosis and intimal thickening in an ex vivo pig coronary artery model.
    Materials and methods
    Results
    Discussion Fas-mediated apoptosis is known to be effective in controlling intimal hyperplasia. Here, we studied the delivery of Fas ligand together with NO donor directly from a polymer coating to facilitate Fas-mediated apoptosis locally. We showed that concentrations of FasL and NO donors released from the EVAc matrix can be tuned to increase SMC apoptosis dramatically without harming endothelium (Fig. 7J–L). Moreover, the EVAc coating on the stents can deliver sufficient amounts of FasL and NO donor to trigger apoptosis only in the SMCs that are in the vicinity of the stent struts, despite arterial-like flow and shear applied during perfusion bioreactor culture (Fig. 8). Furthermore, a 14 day-culture experiment showed that ECs can migrate over the FasL and DetaNONoate-releasing stent coating and form a confluent layer on the stented lumen (Fig. 8 G and H). These results demonstrate the advantage of Fas-DetaNONoate combination over drugs delivered by currently available DES designs [12,13,39]. Our results show that FasL-NO donor combination increased relative IL-6 and IL-8 expression in SMCs, dramatically. This result is not surprising, since IL-6 and IL-8 upregulation in dying SMCs is reported in numerous studies [40,41]. It is well known that IL-6 and IL-8 trigger SMC proliferation, decrease contractile markers, increase monocyte recruitment and upregulate monocyte-chemoattractant protein 1 (MCP-1) in vascular SMCs [40,42]. However, it is also reported that delivery of Fas receptor or Fas ligand gene into the vessel wall reduced intimal hyperplasia, both by triggering vascular SMC apoptosis and by inhibiting T cell infiltration [20,22,28]. Conversely, Fas ligand deficiency was shown to increase T lymphocyte and macrophage infiltration into the vessel wall, and to enhance intimal hyperplasia in injured vessels [43]. Finally, and interestingly, patients with high levels of Fas and Fas ligand in their serum are more resistant to PCI-induced intimal hyperplasia [44]. Thus, our results, together with the findings of the previous studies, warrant further research testing FasL-NO donor releasing stents in animal models.