Effect And Mechanism Of Resveratrol On Myocardial Ischemia With Canine Mammary Tumors Transplanted From Nude Mice

Cardiovascular disease and cancer disease are the two most life-threatening importantdiseases,and they share the same biological mechanism.Recent studies have shown that the focus of cardiovascular disease-tumor research has shifted from theprevention and treatment of single disease to the discussion of the potential relationship between the two.A series of cardiotoxic side effects may be associated with tumor therapy,such as chemoradiotherapy and the most promising immunocheckpoint inhibitors.Canine breast tumor can be used as a preclinical model for human breast cancer research.Resveratrol has the function of inhibiting breast tumors and protecting the heart.The exact mechanism of its action,especially the impact and mechanism of combining the two diseases is still unclear.In this study,we established a model of myocardial ischemia in nude mice transplanted with canine breast tumor to study the effect and mechanism of resveratrol on the combination of these two diseases.Twenty nude mice were randomly divided into five groups.Sixteen nude mice were subcutaneously injected into the cell suspension after the same logarithmic growth phase.The other four were injected with normal saline to inoculate tumor cells.Tumor formation at the site indicates successful construction of the xenograft model.The tumor was administered by gavage on the second day after inoculation.The high-dose group was given80mg/kg,the medium-dose group was given 40mg/kg,the low-dose group was given20mg/kg,the model group was given 0.1ml sodium carboxymethyl cellulose(CMC)+normal saline,and the blank group was given 0.1ml normal saline.After continuous administration for 21d,after the tumor model is successfully established,at the 15th day,each rat was subcutaneously injected with 0.1ml isoproterenol(5mg/kg)to build a myocardial ischemia model,and the model was injected continuously for 7d.Cardiac pathology showed that myocardial fibroblasts had nuclear fragmentation,nuclear lysis,increased collagen fibers,and endocardial shedding,indicating that the myocardial ischemia model was successfully established.After the last administration for 24 hours,the nude mice were sacrificed,and the transplanted tumor tissues and hearts were excised for pathological section preparation.Weigh the tumor to calculate the tumor inhibition rate;Measure the tumor volume;Serum creatine kinase(CK)and lactate dehydrogenase(LDH-L)were detected with the kit;Real-time fluorescence quantitative PCR was used to detect the changes in the expression of Sirt3/Src/Fak pathway related factors in the transplanted tumor tissues and the changes in the expression of sirt3-foxo3 pathway related factors in the heart tissues.1.2×10~6canine breast tumor cells were inoculated on the skin of the right underarm of mice against the back,and visible tumors were developed on the inoculation site of each mouse 7 days later,with the tumorigenesis rate reaching 100%.2.Compared with the model group,the tumor weight and tumor volume of the medium-dose and high-dose groups decreased significantly(P<0.05).The tumor inhibition rates of low,medium and high dose groups were 41.4%,51.5%and 50.7%,respectively.3.HE staining of transplanted tumor showed that,compared with the model group,mitotic phase and nuclear heteromorphism were significantly reduced in the treatment group,the cancer nests were significantly smaller and the inflammatory cells were significantly increased in the medium as well as high dose groups.4.HE staining of heart tissue showed that compared with the model group,myocardial fiber necrosis,myocardial nuclear lysis,deep cytoplasmic staining and endocardial cell shedding were reduced in the treatment group,and ventricular inflammatory cell infiltration near the endocardium was reduced.5.The determination of creatine kinase(CK)and lactate dehydrogenase(LDH-L)by rate method showed that,compared with the model group,the contents of CK and LDH-L were significantly reduced.6.Real-time fluorescence quantitative PCR results showed that mRNA expression levels of Sirt3,Fak and Src in tumor tissues were significantly down-regulated compared with the model group.7.Real-time fluorescence quantitative PCR results showed that,compared with the model group,the mRNA expression level of Sirt3 in heart tissues was significantly up-regulated,and the mRNA expression level of Foxo3 was significantly down-regulated.Resveratrol protects the heart and inhibits tumor growth in nude mice transplanted with canine breast tumor combined with myocardial ischemia.Resveratrol may protect the heart through the Sirt3-Foxo3 signaling pathway,but it may not inhibit tumor growth by regulating the Src/Fak pathway through Sirt3,which may be achieved by down-regulating Fak through other pathways.