PIAS3 deficiency exacerbates the development of atherosclerosis in female ApoE knockout mice

AimTo investigate whether protein inhibitor of activated STAT3 (PIAS3) deficiency exacerbates the occurrence and development of atherosclerosis (As) in female ApoE knockout mice. MethodsPIAS3 gene knockout mice with ApoE^-/-background (PIAS3^-/-/ApoE^-/-) and their littermate PIAS3^+/+/ApoE^-/-mice were bred and fed with a high-fat/high-cholesterol diet for 12 weeks to induce As. Body weight (every week) and plasma lipid levels including total cholesterol, triglyceride, high density lipoprotein cholesterol and non-high density lipoprotein cholesterol (every 4 weeks) of the mice were measured. Oil red O staining, HE staining, immunohistochemistry staining and immunofluorescence staining were performed on mouse aortic tree and frozen sections of aortic root to evaluate the area, cellular composition and stability of As plaques. Moreover, the expression of estrogen receptor α (ERα) and its co-localization with vascular smooth muscle cells (VSMC) in plaques were determined by immunofluorescence staining. ResultsCompared with PIAS3^+/+/ApoE^-/-mice, PIAS3^-/-/ApoE^-/-mice showed no significant differences in body weight, major organ weight (heart, liver, spleen, kidney and epididymal fat) and plasma lipid levels; however, PIAS3 deficiency promoted the formation of As in female PIAS3^-/-/ApoE^-/-mice. Compared with PIAS3^+/+/ApoE^-/-mice, PIAS3^-/-/ApoE^-/-mice showed an increased lipid accumulation and a decreased VSMC content in As plaques (P<0. 05), leading to a decrease in plaque stability. In addition, the expression of ERα in the As plaques of PIAS3^-/-/ApoE^-/-mice was significantly downregulated (P<0. 05), and there was a obvious co-localization between ERα and VSMC. The reduction of VSMC content in PIAS3^-/-/ApoE^-/-mouse plaques might lead to a decrease of ERα expression, thereby weakening the anti-As effect of estrogen. ConclusionPIAS3 deficiency exacerbates the formation of As plaques in female PIAS3^-/-/ApoE^-/-mice, which might be due to the regulatory effect of PIAS3 on ERα expression in plaques.