title: Statins promote the growth of experimentally induced cerebral aneurysms in estrogen-deficient rats.
abstract: OBJECTIVE
  The pathogenesis of cerebral aneurysms is linked to inflammation, degradation of the extracellular matrix, and vascular wall apoptosis. Statins exert pleiotropic effects on the vasculature, independent of their cholesterol-lowering properties. To explore the detailed pathogenesis of cerebral aneurysms, we examined their progression in a rat model and studied whether statins prevent their initiation and growth.
  
  
  METHODS
  Cerebral aneurysms were induced in female rats subjected to hypertension, increased hemodynamic stress, and estrogen deficiency. The development of aneurysm was assessed morphologically on corrosion casts. The effects of pravastatin (5, 25, or 50 mg/kg per day) and of simvastatin (5 mg/kg per day) on their aneurysms were studied. Human brain endothelial cells were also used to determine the effects of pravastatin.
  
  
  RESULTS
  Pravastatin (5 mg/kg per day) reduced endothelial damage and inhibited aneurysm formation; there was an association with increased endothelial nitric oxide synthase (eNOS) levels and a decrease in human brain endothelial cell adhesion molecules. Unexpectedly, 25 mg/kg per day and 50 mg/kg per day pravastatin and 5 mg/kg per day simvastatin promoted aneurysmal growth, and high-dose pravastatin induced aneurysmal rupture. The deleterious effects exerted by these statins were associated with an increase in apoptotic caspase-3 levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, suggesting that statins exert bidirectional effects.
  
  
  CONCLUSIONS
  Our results provide the first evidence that cerebral aneurysm growth is partly associated with apoptosis and issue a warning that statins exert bidirectional effects on cerebral aneurysms. Additional intensive research is necessary to understand better their mechanisms and to identify patients in whom the administration of statins may elicit deleterious effects.
authors: Department of Neurosurgery, Institute of Health Biosciences, The University of Tokushima, Tokushima City, Japan. yoshiteru.tada@hotmail.co.jp
authors: Yoshiteru
authors: Y
authors: Tada
authors: Keiko T
authors: KT
authors: Kitazato
authors: Kenji
authors: K
authors: Yagi
authors: Kenji
authors: K
authors: Shimada
authors: Nobuhisa
authors: N
authors: Matsushita
authors: Tomoya
authors: T
authors: Kinouchi
authors: Yasuhisa
authors: Y
authors: Kanematsu
authors: Junichiro
authors: J
authors: Satomi
authors: Teruyoshi
authors: T
authors: Kageji
authors: Shinji
authors: S
authors: Nagahiro
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002532:Intracranial Aneurysm / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*
chemical_list: D004967:Estrogens; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin