Research On SGLT2 Inhibitor Alleviating Doxorubicin Induced Cardiotoxicity

BackgroundHeart failure is a clinical syndrome characterized by structural and/or functional cardiac abnormalities,including dyspnea,elevated jugular pressure,congestion in the lungs,and swelling of the lower extremities.The overall prevalence of heart failure in the population is about 1-2%.Heart failure not only brings great pain and stress to patients,but also consumes a lot of public medical resources.Adriamycin is a commonly chemotherapeutic drug in the treatment of cancer,which is widely used in solid and non-solid malignant tumors.These drugs can significantly reduce the risk of death in cancer patients,but they can have adverse effects on the cardiovascular system.About 7.25 to 27 percent of cancer patients who was treated using combination chemotherapy die from the cardiotoxicity of chemotherapy drugs.8%-16%of adult cancer patients have clinical or subclinical heart failure after 9 years of chemotherapy.The Syrian Golden Hamster has been used as an animal model to study human disease for more than 60 years.The advantages of the golden hamster as an animal model include a short estrus cycle(4 days)and a shorter gestation period(16 days).and levels of ANP and BNP that are closer to human levels than mouse and rats.The golden hamster will become an excellent model in our experiment.SGLT2 inhibitors are a new class of anti-diabetic drugs.It can be used alone or in combination with other diabetes drugs to improve blood sugar control and lower body weight and blood pressure.Previous studies have shown that SGLT2 inhibitors reduce the risk of cardiovascular events and heart failure in patients with type 2 diabetes.SGLT2 inhibitors have a number of direct or indirect effects that prevent the progression of heart failure.SGLT2 inhibitors may provide cardiovascular benefits by enhancing osmotic diuresis,reducing sympathetic tension,and converting the main metabolism from glucose to fat in the body.MethodsWe first inquired the cardiotoxic effects of doxorubicin at different doses and established a heart failure animal model.Then we investigated the effect of different doses of SGLT2 inhibitors on the cardiotoxic effects induced by high concentrations(2mg/kg)of doxorubicin and the survival curves.Next,We investigated the therapeutic effect of SGLT2 inhibitors on the cardiotoxicity of doxorubicin at low concentration doses(1mg/kg).Several golden hamsters were divided in to four groups named Group A(PBS),Group B(DOX),Group C(PBS-SGLT2),and Group D(DOX-SGLT2).DOX-SGLT2 group:DOX group was given intraperitoneal injection of lmg/kg DOX once a week for 6 weeks,while PBS-SGLT2 group and PBS group were given intraperitoneal injection of PBS.For the next four weeks,DOX-SGLT2 and PBS-SGLT2 groups were given SGLT2 inhibitor gavage at 5mg/kg once daily for 4 weeks,while DOX and PBS groups were given solution gavage.Then we performed echocardiography on the hamsters to analyze the ejection fraction of the heart.All hamsters were sacrificed and we measure and compare the ratio of heart weight to tibial length.Quantitative real-time fluorescent PCR(qRT-PCR)was performed to determine Brain natriuretic peptide(BNP)and Western Blot was used to determine LC3B and Parl.He and Masson staining were performed on hamster heart tissue to observe and compare the fibrosis of each group.ResultsThe effect of SGLT2 inhibitors on the treatment of high dose DOX is not obvious.In studies of low dose doxorubicin:hamsters in the B and D groups were successfully induced into a heart failure model with significantly lower left ventricular ejection fraction(41%)and a lower mortality rate(11%).After gavage with SGLT2 inhibitor,the ejection fraction of hamsters in group D recovered to normal level.Compared with group B,the BNP level of hamsters in group D decreased significantly,which was similar to that in group C.Masson staining of the heart tissue showed 10%less fibrosis area in group D than in group B.The results of cardiac ultrasound showed that the mean ejection fraction in group D increased to more than 60%after treatment,which was more than 20%higher than that in group B.We also found that SGLT2 inhibitors can significantly enhance autophagy with increasing the levels of protein LC3BII and decrease apoptosis with reducing C-caspase.Conclusions:Syrian golden hamsters would become heart failure model after intraperitoneal injection of doxorubicin at low dose lmg/kg once a week for six weeks.SGLT2 inhibitor has a very good therapeutic effect on doxorubicin-induced heart failure hamsters,which can significantly reduce BNP and increase ejection fraction,and the better dose is 5mg/kg.SGLT2 inhibitors alleviate the level of myocardial injury caused by doxorubicin by enhancing autophagy and Anti-apoptotic effect.