title: mTOR inhibition: a promising strategy for stabilization of atherosclerotic plaques.
abstract: Statins are currently able to stabilize atherosclerotic plaques by lowering plasma cholesterol and pleiotropic effects, but a residual risk for atherosclerotic disease remains. Therefore, effective prevention of atherosclerosis and treatment of its complications is still a major clinical challenge. A large body of evidence indicates that mammalian target of rapamycin (mTOR) inhibitors such as rapamycin or everolimus have pleiotropic anti-atherosclerotic effects so that these drugs can be used as add-on therapy to prevent or delay the pathogenesis of atherosclerosis. Moreover, bioresorbable scaffolds eluting everolimus trigger a healing process in the vessel wall, both in pigs and humans, that results in late lumen enlargement and plaque regression. At present, this phenomenon of atheroregression is poorly understood. However, given that mTOR inhibitors suppress cell proliferation and trigger autophagy, a cellular survival pathway and a process linked to cholesterol efflux, we hypothesize that these compounds can inhibit (or reverse) the basic mechanisms that control plaque growth and destabilization. Unfortunately, adverse effects associated with mTOR inhibitors such as dyslipidemia and hyperglycemia have recently been identified. Dyslipidemia is manageable via statin treatment, while the anti-diabetic drug metformin would prevent hyperglycemia. Because metformin has beneficial macrovascular effects, this drug in combination with an mTOR inhibitor might have significant promise to treat patients with unstable plaques. Moreover, both statins and metformin are known to inhibit mTOR via AMPK activation so that they would fully exploit the beneficial effects of mTOR inhibition in atherosclerosis.
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. Electronic address: wim.martinet@uantwerpen.be.
authors.forename: Wim
authors.initials: W
authors.lastname: Martinet
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Hans
authors.initials: H
authors.lastname: De Loof
authors.affiliation: Laboratory of Physiopharmacology, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
authors.forename: Guido R Y
authors.initials: GRY
authors.lastname: De Meyer
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors; D020341:Absorbable Implants; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D002784:Cholesterol / Q000097:blood; D002986:Clinical Trials as Topic; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D054855:Drug-Eluting Stents; D050171:Dyslipidemias / Q000139:chemically induced / Q000517:prevention & control; D000068338:Everolimus; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011817:Rabbits; D011973:Receptors, LDL / Q000172:deficiency; D012422:Rupture, Spontaneous / Q000517:prevention & control; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D054457:Tissue Scaffolds; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D014280:Triglycerides; D008687:Metformin; D002784:Cholesterol; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus
keywords: Atherosclerosis; Autophagy; Drug-eluting stent; Everolimus; Rapamycin; mTOR