4周生酮饮食通过调控HMGB1-NLRP3通路预防DOX诱导的小鼠心肌毒性OA

AIM:To investigate the preventive effects of low-carbohydrate ketogenic diet(KD)on doxorubi-cin(DOX)-induced myocardial toxicity in mice and its underlying mechanisms.METHODS:Thirty-two male mice(C57BL/6)were randomly divided into four groups:control(CON)group,DOX model group(DOX group),KD interven-tion group(KD group),and KD+DOX group,with 8 mice per group.The mice were fed a regular diet or KD for four weeks,followed by a single intraperitoneal injection of normal saline or DOX(20 mg/kg).During the intervention period,the body weight(BW),blood ketone(BK)and blood glucose(BG)levels of the mice were measured at regular intervals.Four weeks after the intervention,an intraperitoneal glucose tolerance test was performed.The cardiac function indicators of the mice were detected by small animal ultrasound imaging system.The serum myocardial injury enzymes,four items of blood lipids and oxidative stress indicators were detected by an automatic biochemical analyzer and enzyme-linked immu-nosorbent assay.Hematoxylin-eosin staining was used to observe the morphological changes of myocardial tissue,and Siri-us red staining was used to evaluate the degree of myocardial fibrosis.Western blot was used to detect the expression levels of oxidative stress,inflammation,fibrosis-related proteins and high mobility group box 1(HMGB1)-nucleotide-binding oligomerization domain-like receptor protein 3(NLRP3)pathway in myocardial tissue.RESULTS:Four-week KD inter-vention increased BK levels in mice but decreased BG levels and BW(P<0.01).Cardiac function indicators,such as ejection fraction and fractional shortening,were significantly better in the KD+DOX group than in the DOX group(P<0.01).Hematological and histological results showed that KD alleviated DOX-induced myocardial injury and fibrosis(P<0.01).Western blot results revealed that the levels of oxidative stress indicators(NADPH oxidase 4 and inducible nitric oxide synthase),inflammatory response indicators(tumor necrosis factor-α and interleukin-11),and fibrosis indicators(collagen type I,collagen type III,and α-smooth muscle actin)were significantly lower in KD+DOX group than those in DOX group(P<0.01).In terms of molecular mechanisms,the expression levels of HMGB1-NLRP3 pathway in the myo-cardium of the KD+DOX group were significantly lower than those in the DOX group(P<0.01).CONCLUSION:Four-week KD intervention reduced BG and increased BK levels in mice,and prevented DOX-induced myocardial injury,oxida-tive stress,inflammatory response,and fibrosis.Reduction of HMGB1 and NLRP3 expression suggests that the underlying mechanism involve inhibition of the HMGB1-NLRP3 pathway in the myocardium.