PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization: potential implications for drug-eluting stent design

European Heart Journal
Erik W HolyFelix C Tanner

Abstract

Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury. PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the β-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NF...Continue Reading

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Citations

Jan 23, 2016·Journal of Cardiovascular Translational Research·Belay Tesfamariam
Mar 24, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Belay Tesfamariam
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Oct 8, 2016·Journal of the American College of Cardiology·Erik W HolyFelix C Tanner
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Nov 13, 2019·Journal of Cellular and Molecular Medicine·Chi-Yu ChenShing-Jong Lin
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Oct 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Pierre-Alexandre LaurentMarie-Pierre Gratacap
Oct 28, 2018·Journal of Cardiovascular Translational Research·Belay Tesfamariam

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