Title
Everolimus triggers cytokine release by macrophages : rationale for stents eluting everolimus and a glucocorticoid Everolimus triggers cytokine release by macrophages : rationale for stents eluting everolimus and a glucocorticoid
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Medicine and Health Sciences
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Publication type
article
Publication
Dallas, Tex. ,
Subject
Pharmacology. Therapy
Human medicine
Source (journal)
Arteriosclerosis, thrombosis, and vascular biology / American Heart Association. - Dallas, Tex., 1995, currens
Volume/pages
32(2012) :5 , p. 1228-1235
ISSN
1079-5642
1524-4636
ISI
000303195100028
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
Objective-: Stent-based delivery of the mammalian target of rapamycin (mTOR) inhibitor everolimus is a promising strategy for the treatment of coronary artery disease. We studied potential adverse effects associated with mTOR inhibition. Methods and Results-: Macrophages in culture were either treated with everolimus or starved to inhibit mTOR. Everolimus led to inhibition of protein translation, activation of p38 MAPK, and the release of proinflammatory cytokines (eg, IL-6, TNF[alpha]) and chemokines (eg, MCP1, Rantes) before induction of autophagic death. These effects were also observed with rapamycin, but not after starvation. Everolimus-induced cytokine release was similar in macrophages lacking the essential autophagy gene Atg7 but was inhibited when macrophages were cotreated with p38 MAPK inhibitor SB202190 or the glucocorticoid clobetasol. Combined stent-based delivery of clobetasol and everolimus in rabbit plaques downregulated TNF[alpha] expression as compared with everolimus-treated plaques but did not affect the ability of everolimus to induce macrophage clearance. Conclusion-: mTOR inhibition by everolimus triggers cytokine release in macrophages through inhibition of protein translation and p38 activation. These findings provide a rationale for combined local treatment of atherosclerotic plaques with everolimus and an anti-inflammatory agent.
E-info
https://repository.uantwerpen.be/docman/iruaauth/d528ef/c02fa913b18.pdf
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