title: Pioglitazone increases macrophage apoptosis and plaque necrosis in advanced atherosclerotic lesions of nondiabetic low-density lipoprotein receptor-null mice.
abstract: BACKGROUND
  Thiazolidinediones (TZDs), which have actions that involve both peroxisome proliferator-activated receptor (PPAR)-gamma-dependent and -independent effects, improve insulin sensitivity in type II diabetes and inhibit early atherogenesis in mice. However, the effects of TZDs on advanced lesion progression are unknown.
  
  
  RESULTS
  Pioglitazone and rosiglitazone enhanced macrophage apoptosis by a number of stimuli, including those thought to be important in advanced atherosclerosis. Macrophage death was not enhanced by non-TZD PPARgamma activators, and TZD-induced apoptosis was still observed in PPARgamma-deficient macrophages. In wild-type macrophages, death enhancement was associated with reduced activation of the cell-survival mediator nuclear factor-kappaB. TZDs also increased the ability of macrophages to phagocytically clear apoptotic cells, which is proposed to protect against plaque necrosis in advanced lesions. The mechanism of this effect was complex, involving both PPARgamma-dependent and -independent mechanisms. To explore the net effect on advanced atherosclerosis in vivo, Ldlr-/- mice were fed a nondiabetogenic cholesterol-enriched diet to promote midstage lesions. Then, pioglitazone was administered with the diet for an additional 10 weeks. Aortic root lesions from the pioglitazone-treated mice showed a substantial increase in apoptotic cells and plaque necrosis compared with lesions from non-drug-treated mice.
  
  
  CONCLUSIONS
  The potential atheroprotective effects of TZDs conferred by insulin sensitization may be partially offset by adverse effects on advanced atherosclerosis. Because the mechanisms of the beneficial and proposed adverse effects may differ, these findings have potentially important implications for drug optimization.
authors.affiliation: Department of Medicine, Columbia University, 630 W 168th St, New York, NY 10032, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Thorp
authors.forename: George
authors.initials: G
authors.lastname: Kuriakose
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2; D005260:Female; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009336:Necrosis; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D011973:Receptors, LDL / Q000235:genetics*; D045162:Thiazolidinediones / Q000633:toxicity*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D011973:Receptors, LDL; C498144:Rela protein, mouse; D045162:Thiazolidinediones; D051996:Transcription Factor RelA; D002784:Cholesterol; D000077205:Pioglitazone