Everolimus-induced mTOR inhibition selectively depletes macrophages in atherosclerotic plaques by autophagy.
Current pharmacological approaches to stabilize nonobstructive rupture-prone atherosclerotic plaques have only partially reduced the incidence of acute coronary syndromes and sudden death. Macrophages in these vulnerable plaques play a pivotal role in plaque destabilization, whereas smooth muscle cells promote plaque stability. In a recent study, we report that implantation of stents eluting everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in atherosclerotic arteries of cholesterol-fed rabbits, led to a marked reduction in macrophage content without altering the amount of smooth muscle cells. Our in vitro studies showed that treatment of macrophages and smooth muscle cells with everolimus induced inhibition of translation of both cell types. However, cell death occurred only in macrophages and was characterized by bulk degradation of long-lived proteins, processing of microtubule associated protein light chain 3 (LC3), and cytoplasmic vacuolization, which are all markers of autophagy. Everolimus-induced autophagy was mediated by mTOR inhibition because cell viability was not affected using tacrolimus, an mTOR independent everolimus-analogue. These results provide proof-of-principle that macrophages in the vascular wall can be selectively cleared via induction of autophagy by mTOR inhibition. Therefore, stent-based delivery of an mTOR inhibitor may be a promising novel strategy for treatment of vulnerable atherosclerotic plaques.
Martinet
Wim
W
Division of Pharmacology, University of Antwerp, Wilrijk, Belgium. wim.martinet@ua.ac.be
Verheye
Stefan
S
De Meyer
Guido R Y
GR
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology / Q000628:therapy*; D001343:Autophagy; D002784:Cholesterol / Q000378:metabolism; D004032:Diet; D000068338:Everolimus; D008264:Macrophages / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D011817:Rabbits; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D015607:Stents; D058570:TOR Serine-Threonine Kinases
D002784:Cholesterol; D000068338:Everolimus; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus