GENDER SPECIFIC DIFFERENCES IN A NEW APOE-/-:INS2+/AKITA MOUSE MODEL OF HYPERGLYCEMIA-INDUCED ATHEROSCLEROSIS

Abstract

PURPOSE: People with diabetesmellitus have a 2 to 4-fold increased risk of cardiovascular disease (CVD). Despite a vast amount of research, the underlying mechanisms that predispose individuals with diabetes to the development of CVD are unclear. Thus, to further our understanding of how diabetes promotes CVD and to begin to delineate how gender may influence pathogenesis, we have established, characterized and manipulated a new model of hyperglycemia-induced atherosclerosis: the apoE:Ins2 mouse. METHODS: Ins2 is anautosomaldominantmutation(C96Y)that induces juvenile-onset hyperglycemia in the absence of obesity. Ins2 Akita male mice were crossed to apoE female mice, which spontaneously develop atherosclerosis. At 5 weeks of age, male/female apoE:Ins2 mice were castrated/ovariectomized and fed a standard chow diet until the 25 weeks of age whenmice were euthanized and organs were harvested. Metabolic parameters and atherosclerotic developmentweremonitored and analyzed through the whole study. RESULTS: Male apoE:Ins2 developed persistent hyperglycemia. At 25 weeks of age, lesions from hyperglycemic mice were 3-4 times larger, with significantly larger necrotic cores, and presented calcifiedregions,comparedtonormoglycemicapoEmales.Castrated maleapoE:Ins2miceshowedareductioninbloodglucoselevels which correlated to a lack of testosterone, an improvement of several metabolic parameters, and a partial amelioration of atherosclerosis. Female apoE:Ins2 presented transient hyperglycemia that normalized by 15 weeks of age. Despite the transient hyperglycemia, larger atherosclerotic lesions were observed at 15 weeks of age compared to apoE females. Ovariectomized female apoE:Ins2 Akita mice presented chronic hyperglycemia and accelerated atherosclerosis relatively similar to male apoE:Ins2 mice. Estradiol levels were compensated in all ovariectomized mice suggesting a role for progesterone in the maintenance of euglycemia. CONCLUSION: We have developed gender-specific models of chronic and transient hyperglycemia-induced atherosclerosis. In both genders, sexual hormones impacted atherosclerosis through at least 3 mechanisms: i) the effect on insulin secretion and its regulation of the glucose levels, ii) the effect on lipid metabolism and the bioavailability of atherogenic lipoprotein particles, and iii) the protective effect directly exerted on the vasculature. CDA