PERK inhibition mitigates restenosis and thrombosis - a potential low-thrombogenic anti-restenotic paradigm

Wang, B.; Zhang, M.; Urabe, G.; Chen, G.; Wheeler, D.; Dornbos, D.; Huttinger, A.; Huang, Y.; Nimjee, S.; Gong, S.; Guo, L.; Kent, K. C.

doi:10.1101/581397

bioRxiv · 10.1101/581397

PERK inhibition mitigates restenosis and thrombosis - a potential low-thrombogenic anti-restenotic paradigm

Wang, B.·Zhang, M.·Urabe, G.·Chen, G.·Wheeler, D.·Dornbos, D.·Huttinger, A.·Huang, Y.·Nimjee, S.·Gong, S.·Guo, L.·Kent, K. C.

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Abstract

BackgroundDrug-eluting stents (DES) represent the main-stream management of restenosis following treatments of occlusive cardiovascular diseases. However, DES cannot eliminate instent restenosis yet exacerbate thrombogenic risks. To achieve dual inhibition of restenotic smooth muscle cell (SMC) de-differentiation/proliferation and thrombogenic endothelial cell (EC) dysfunction, a common target in both cell types, has been long-sought after. We evaluated the potential of protein kinase RNA-like endoplasmic reticulum kinase (PERK) as such a target for low-thrombogenic anti-restenotic intervention.\n\nMethods and ResultsWe used a rat angioplasty model of restenosis and a FeCl3-induced mouse model of thrombosis. Loss-or gain-of-function was achieved by PERK inhibition (GSK2606414, siRNA) or overexpression (adenovirus). Restenosis was robustly mitigated by GSK2606414 administered either via injected (i.v.) lesion-homing platelet membrane-coated nanoclusters or a perivascular hydrogel; it was enhanced by PERK transgene. Whereas PERK inhibition blocked, its overexpression exacerbated PDGF-induced human aortic SMC de-differentiation (reduced smooth muscle -actin or SMA) and proliferation (BrdU incorporation). Further, PERK activity promoted STAT3 activation but inhibited SRF transcriptional (luciferase) activity; its protein co-immunoprecipitated with STAT3 and also MRTF-A, the SRF activator for SMA transcription. Importantly, PERK inhibition also prevented TNF-induced impairment of human EC growth and upregulation of thrombogenic tissue factor, both in vitro and ex vivo. In vivo, oral gavage of GSK2606414 preserved ~50% of the normal blood flow 60 min after FeCl3-induced vascular injury.\n\nConclusionsPERK inhibition is dual beneficial in mitigating restenosis and thrombosis, thus implicating a potential design for anti-restenotic intervention to overcome the thrombogenicity of DES.

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Wang, B., Zhang, M., Urabe, G., Chen, G., Wheeler, D., Dornbos, D., Huttinger, A., Huang, Y., Nimjee, S., Gong, S., Guo, L., Kent, K. C.. 2019-03-18. PERK inhibition mitigates restenosis and thrombosis - a potential low-thrombogenic anti-restenotic paradigm. https://doi.org/10.1101/581397

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