We ARE different after all: Diabetic, obese and atherosclerotic rats have sex‐specific disease progression

Abstract

Atherosclerosis is the leading cause of death and disability in the world. Diabetes affects 1 in 10 adults in the US, with 90–95% of the cases being type 2 (type 2‐DM). Patients with diabetes have a 4‐fold increase in the risk of developing coronary arterial disease (CAD). Morbidity and mortality related to vascular disease are worse in diabetics. Therefore, there is a pressing need to develop better ways to diagnose, treat, and study the pathophysiology of diabetic atherosclerosis. Modifiable health risks are consistently outlined but sex‐dependent risk is non‐modifiable and can determine disease outcome. Males and females experience different degrees of CAD. Multiple studies, including the PROMISE trial, reiterate the need to study sex‐specific cardiometabolic‐protective targets. Our laboratory has shown that apoE−/−; leprfa/fa(ZDF) CRISPR‐Cas generated rats are severely dyslipidemic and that there is an interaction between the Lepr and apoE genotypes. Additionally we have shown mild atherosclerosis in young rats fed a high‐fat diet for little over 3 weeks. Our hypothesis is that our obese, dyslipidemic, atherosclerotic and diabetic rats will present with sex‐dependent accelerated development of atherosclerosis, recapitulating common comorbidities of type 2‐DM by synergistic effect between the apoE−/− and Leprfa/fa genotype.METHODSMale/female apoE−/−; lepr+/?(LZ) and apoE −/−; ZDF rats were fed regular chow or high‐fat diet (0.21% cholesterol, 21% fat) for 18 weeks (n:6/group) starting at 12 weeks of age. Weight, glycemia, lipid and blood chemistry was performed as well as apoE‐KO confirmation via immunoblot and oral glucose tolerance test (type 2‐DM diagnosis). Serum was collected at 12 and 30 weeks of age. Whole aortas (en face) and brachiocephalic tree were harvested, stained with Oil Red O (ORO) for histologic analysis.RESULTSAll lipids are higher in both ZDF males and females compared to LZ. Total cholesterol and LDL were ~5 fold greater in ZDF females compared to males at baseline and 18 weeks of HFD. Kidney function was altered in rats fed a HFD, ZDF rats and particularly males. Elevated AST and ALT evidenced liver steatosis in rats under HFD. Diabetic males show uncontrolled chronic severe hyperglycemia while diabetic females control hyperglycemia better than males. En face ORO showed apoE−/−; LZ males under HFD have the highest percentage of atherosclerotic lesion (21%), female apoE−/− LZ (10.5%) and apoE−/−; ZDF (12.6%) under a HFD do not show differences between them.CONCLUSIONSSerum chemistry differences observed at baseline and post‐18 weeks of HFD appears to drive severe dyslipidemia in our model. Females have lower hyperglycemia and more severe hypercholesterolemia than males but do not appear to have increased amount of lipid deposit on the vasculature compared to males. apoE−/−; ZDF male rats have severe chronic hyperglycemia with less hyperlipidemia compared to females. These findings will lead our future studies to study possible athero‐protective mediators in females or worst‐disease predictors in males.Support or Funding InformationNORC‐PPF(P30 DK056350) to EMB.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.