title: Sex-Specific Differences in an ApoE(-/-):Ins2(+/Akita) Mouse Model of Accelerated Atherosclerosis.
abstract: Diabetic patients have a twofold to fourfold increased risk of cardiovascular disease. Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of cardiovascular disease are unclear. To further our understanding of how diabetes promotes atherosclerosis, we have established, characterized, and manipulated a new model of hyperglycemia-induced atherosclerosis: the apolipoprotein E-deficient (ApoE(-/-)):Ins2(+/Akita) mouse. All mice were fed a standard chow diet. Male ApoE(-/-):Ins2(+/Akita) mice developed chronic hyperglycemia, which significantly accelerated atherosclerosis. Female ApoE(-/-):Ins2(+/Akita) mice presented hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, advanced atherosclerosis was observed at 15 weeks of age compared with ApoE(-/-) females. To better understand these differences, subsets of mice were castrated or ovariectomized at 5 weeks of age. Castrated ApoE(-/-):Ins2(+/Akita) mice showed a reduction in blood glucose levels that correlated with the amelioration of atherosclerosis. Interestingly, castrated normoglycemic ApoE(-/-) mice developed larger atherosclerotic lesions than sham-operated on controls. Ovariectomized ApoE(-/-):Ins2(+/Akita) mice presented chronic hyperglycemia, and atherosclerosis appeared to be advanced. We have characterized the distinctive sex-specific phenotypes exhibited by the ApoE(-/-):Ins2(+/Akita) mouse model and present evidence for the action of sex hormones on pancreatic β-cell function and the vasculature that affect the regulation of blood glucose levels and the development of atherosclerosis. This model will provide a test bed to further delineate these effects.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Venegas-Pino
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Wang
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Heidi K
authors.initials: HK
authors.lastname: Stoute
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Singh-Pickersgill
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Brian Y
authors.initials: BY
authors.lastname: Hong
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: geoff.werstuck@taari.ca.
authors.forename: Geoff H
authors.initials: GH
authors.lastname: Werstuck
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology*; D002369:Castration; D003920:Diabetes Mellitus; D004195:Disease Models, Animal; D005260:Female; D006943:Hyperglycemia / Q000150:complications*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010052:Ovariectomy; D012727:Sex Characteristics
chemical_list: D001057:Apolipoproteins E; C561967:Ins2 protein, mouse; D007328:Insulin