A rapamycin derivative, biolimus, preferentially activates autophagy in vascular smooth muscle cells

Abstract

Although rapamycin is a well-known conformational inhibitor of mTORC1, it is now widely used for treating arterial restenosis. Various rapamycin analogues (rapalogue) have been made for applying to drug-eluting stents. Here we show that two major rapalogues, everolimus and biolimus, exert a differential effect on the mTORC1-mediated signaling pathways in vascular smooth muscle cells. In balloon-injured carotid arteries, both rapalogues strongly inhibit neointimal hyperplasia. Signaling pathway analyses reveal that everolimus exert cytotoxicity by increasing cellular reactive oxygen species and consequently reduce energy metabolism. By contrast, biolimus confers a preferential induction of autophagy by more strongly activating major autophagy regulator, ULK1, in vascular smooth muscle cells than everolimus does. As a consequence, the implantation of biolimus-eluting stent reduces endothelial loss, which in turn reduces inflammation, in porcine coronary arteries. Thus, this study reveals that a chemical derivatization can cause a change among mTORC1-dependent signaling pathways in vascular smooth muscle cells, thereby enabling to elicit a differential efficacy on arterial restenosis.

Causative Links between Protein Aggregation and Oxidative Stress: A Review

“…The rapamycin derivative, Rilmenidine, which is protective against oxidative cytotoxicity [85], was also shown to increase autophagy, despite failing to decrease the accumulation and aggregation of SOD1 in a mouse ALS model [86]. Another rapamycin derivative, biolimus, was also shown to be capable of activating autophagy efficiently in smooth muscle cells [87]. Most of these drugs have been shown to play on the oxidative balance within cells.…”

TAK1 accelerates transplant arteriosclerosis in rat aortic allografts by inducing autophagy in vascular smooth muscle cells

“…Our results revealed the induction of TAK1mediated autophagy in the neointima. In addition, an autophagy accelerator, biolimus, and an autophagy inhibitor, 3-MA, both suppressed neointima formation [15,[48][49][50]. In addition, the deletion of Atg7 and Beclin1 accelerated neointima formation after vascular injury (**p < 0.01 vs Control, # p < 0.05 vs PDGF-BB, ## p < 0.01 vs PDGF-BB.)…”

Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions

“…The antidepressant drug indatraline promotes cell growth inhibition of smooth muscle cells, inhibition of neointimal hyperplasia, and thus relieves restenosis in rats ( Cho et al., 2016 ). Whereas indatraline targets autophagy via the AMPK/mTOR pathway ( Cho et al., 2016 ), rapalog biolimus inhibits mTORC1 signaling leading to mitigation of restenosis-mediated autophagy ( Kim et al., 2018 ). Recently, the third generation of mTORC1 inhibitor, RapaLink-1, showed superior effects on the mTOR pathway, resulting in activation of autophagy and protection from thrombosis-related diseases including atherosclerosis, antiphospholipid syndrome (APS), and stroke ( Mu et al., 2020 ).…”