不同剂量多柔比星诱导衰老小鼠模型的构建OA

Objective To establish rapid-aging and cardiac-aging mouse models by intraperitoneal injection of doxorubicin(DOX)at different doses and frequencies,to optimize model-evaluation indices,and provide disease-model support for anti-aging drug evaluation.Methods(1)For the rapid-aging model,mice were divided into model 1(5 mg/kg,once every 7 d),model 2(8 mg/kg,once every 10 d),model 3(8 mg/kg,once every 7 d),model 4(10 mg/kg,once every 10 d),and model 5(10 mg/kg,once every 7 d)groups.DOX was administered by three intraperitoneal injections and mice were observed continuously for 60 d to record survival rate.(2)For the cardiac-aging model,mice were divided into control,model-1(2 mg/kg),model-2(5 mg/kg),model-3(8 mg/kg),and model-4(10 mg/kg)groups.Injections were given twice,once every 10 d,for 30 d.After completion,ejection fraction(EF),fractional shortening(FS),and peak blood flow velocity were evaluated by small animal high-frequency ultrasound imaging.Serum levels of creatine kinase-MB(CK-MB),lactate dehydrogenase(LDH),interleukin(IL)-6,and IL-1β,and myocardial-tissue levels of superoxide dismutase(SOD),malondialdehyde(MDA),glutathione peroxidase(GSH-Px),succinate dehydrogenase,and catalase were measured.Myocardial tissue pathology,fibronectin,β-galactosidase staining(β-gal),and p16 protein,along with other cardiac aging-related indicators,were assessed.Results(1)In the rapid-aging mouse model,body mass and survival rate showed significant downward trends in all modeling groups.Decreases in body mass and survival rate became more pronounced with increasing DOX dose and shortened modeling interval.(2)In the cardiac-aging model,compared with the control group,DOX 2,5,8,and 10 mg/kg significantly increased LDH levels(P＜0.01)and decreased GSH-Px activity(P＜0.05 or P＜0.01),and DOX 5,8,and 10 mg/kg significantly decreased body mass(P＜0.01),EF,FS,and peak blood flow velocity(P＜0.05 or P＜0.01).Serum IL-6 levels were significantly increased,SOD content was significantly decreased,and β-galactosidase and p16 protein expression levels were significantly elevated(P＜0.05 or P＜0.01).Myocardial tissue showed hydropic and vacuolar degeneration.DOX 8 and 10 mg/kg also significantly increased CK-MB levels and cardiac fibrosis,and DOX 10 mg/kg increased IL-1βand MDA contents(P＜0.01).Conclusions Intraperitoneal injection of DOX 10 mg/kg once every 10 d for three injections successfully established a rapid-aging mouse model,while intraperitoneal injection of DOX 5 or 8 mg/kg once every 10 d for two injections successfully established a cardiac-aging mouse model,which induced changes in cardiac function,myocardial enzymes,inflammation,oxidative stress,aging markers,cardiac pathology,and fibrosis consistent with physiological and pathological characteristics of cardiac aging.