title: Estrogen-dependent activation of neutral cholesterol ester hydrolase underlying gender difference of atherogenesis in apoE-/- mice.
abstract: OBJECTIVE
  Mechanisms underlying gender difference of atherogenesis were investigated focusing on direct effects of estrogen on the artery.
  
  
  METHODS
  First, male and female apoE(-/-) mice were fed an atherogenic diet for 16 weeks from 10 weeks of age. Second, female apoE(-/-) mice were ovariectomized (ovx) or sham operated at 8 weeks of age, and 2-weeks afterwards, one-third of each ovx-group received conjugated equine estrogens (CEE) (0, 2.5 or 5.0 μg/day) for 16 weeks. Atherosclerotic lesions were examined after experimental periods. To clarify anti-atherogenic effect of 17β-estradiol (E2) on artery, neutral cholesteryl ester hydrolase (N-CEase) activity in aorta and peritoneal macrophages, and E2-treated J774A.1 cells were measured.
  
  
  RESULTS
  First, atherosclerotic lesion in female mice was significantly less than male mice without any changes in serum lipids and lipoprotein profile. N-CEase activity in aorta and peritoneal macrophages in female mice was significantly higher than male mice. Second, atherosclerotic lesion in ovx-group was significantly greater than sham-group. CEE-replacement to ovx-group decreased atherosclerotic lesion in a dose-dependent manner. N-CEase activity in aorta and peritoneal macrophages was decreased in ovx-group compared to sham-group, and restored by CEE-replacement in macrophages. To study detailed mechanisms, J774A.1 cells were treated with E2. E2 significantly increased N-CEase activity, and cAMP-dependent protein kinase (A-kinase) type II activity and the protein in cytosol fraction without any changes of total protein of A-kinase type II.
  
  
  CONCLUSIONS
  These results suggest that gender difference of atherogenesis is partly accounted for activation of N-CEase through estrogen-dependent translocation of A-kinase type II in macrophages.
authors.affiliation: Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka-shi, Shizuoka 422-8526, Japan. tyschiba@nih.go.jp
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Chiba
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ikeda
authors.forename: Keizo
authors.initials: K
authors.lastname: Umegaki
authors.forename: Takako
authors.initials: T
authors.lastname: Tomita
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D054746:Cyclic AMP-Dependent Protein Kinase Type II / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004958:Estradiol / Q000378:metabolism*; D015914:Estrogen Replacement Therapy; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage; D005260:Female; D008055:Lipids / Q000097:blood; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010052:Ovariectomy; D021381:Protein Transport; D012737:Sex Factors; D002787:Sterol Esterase / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D004966:Estrogens, Conjugated (USP); D008055:Lipids; C040661:apolipoprotein E1; D004958:Estradiol; D054746:Cyclic AMP-Dependent Protein Kinase Type II; C514712:Nceh1 protein, mouse; D002787:Sterol Esterase