Influence of Sex on the Response to Anti-Inflammatory Treatment and on Survival in a Murine Model of Diet-Induced Coronary Artery Disease

Background and Aims: Cardiovascular risk considerably increases in women after menopause, even surpassing that of men, suggesting an effect of age and sex (1-3). We proposed to study sex-dependent differences on survival, systemic inflammation and monocyte population and its response to anti-inflammatory treatment in young male and female mice, using a diet-induced model of atherosclerosis. Methods: Male and female SRB1 KO/apoEhypomorphic mice, aged 2-3 months, were randomly assigned to 2 groups: Control (HFD-Control) and minocycline (HFD-MIN). Minocycline was administered in the drinking water at a dose of 0.05 mg/mL. Atherosclerosis was induced by feeding an atherogenic diet (15% fat, 1.25% cholesterol, 0.5% cholate). Survival was evaluated by the Kaplan-Meier method. Systemic inflammation and monocyte populations were compared by Mann–Whitney U test and PCA analysis. Results: Female mice have a slightly better survival than male mice when fed an atherogenic diet (P=0.12). Minocycline improved survival in male by 35% (P=0.006) and 33% in female mice (P=0.01). Minocycline significantly reduced IL-6 levels (P=0.04) and Ly-6Chigh subset (P= 0.006) and increased Ly6Clow subset (P= 0.006) in male mice without affecting total blood monocytes (P= 0.3). Male and female fed with HFD clustered in different groups; however, after minocycline intervention, were indistinguishable.View Large Image Figure ViewerDownload Hi-res image Download (PPT)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusions: High fat diet decreased the survival and caused early death in this model; however, female have a slightly better survival than male mice. Minocycline improved survival in both, however it had a higher impact on systemic inflammation in male mice by reducing plasma IL-6 levels and shifting toward a more “reparative” phenotype on circulating monocyte subsets.