|Other Abstract||Objective: Heart failure is the final stage of cardiovascular disease, gradually becoming an important global public health problem, acute myocardial infarction is the most common cause of heart failure, the incidence of heart failure patients after acute myocardial infarction is high, with the continuous progress of the treatment of myocardial infarction, the incidence of heart failure after myocardial infarction has a downward trend.Ventricular remodeling is the basic pathological process of heart failure after acute myocardial infarction, which is driven by pathological cardiomyocyte hypertrophy, apoptosis, fibroblast proliferation and fibrosis.Fibrosis is an important phenotype leading to late remodeling. A large number of myocardial fibrosis changes lead to enlarged heart cavity, decreased cardiac compliance, and decreased cardiac function.Sodium glucose transporter 2 inhibitors themselves are an effective hypoglycemic agent, but they can benefit patients with heart failure and reduce ventricular remodeling. However, the mechanism by which SGLT2 inhibitors reduce ventricular remodeling remains unclear.In this study, the effects of SGLT2 inhibitor dagliquin on ventricular remodeling, TGF-βexpression and p38 phosphorylation in mice after acute myocardial infarction were investigated in vivo.
Methods: Forty-seven C57 healthy male mice were randomly divided into four groups: the first normal control group (control) n=11, the second sham-operated group (Sham) n=11, the third surgical group (MI) n=14, the fourth dagliflozin intervention + MI group (DAPA+MI) n=11, the control group was left untreated, the sham group was opened and ligated without coronary artery only, and the other three groups were opened and ligated with coronary artery. In the DAPA+MI group, dagliflozin (1 mg/kg/day) was administered by gavage, and in the other three groups, saline was administered in equal amounts daily. Six groups of data were examined;ELISA was used to detect the changes of plasma NT-proBNP and TGF-βconcentrations;HE staining was used to detect the changes of cardiomyocytes in each group, and Masson staining was used to detect the degree of myocardial fibrosis in each group;immunohistochemistry was used to detect the changes of TGF-βand phosphorylated p38 positive area, and protein blotting was used to detect the TGF-βand phosphorylated p38 protein expression changes.
Results: Four weeks after surgery, there were no significant differences in cardiac function and cardiac structure, inflammatory cell exudation, and cardiac fibrosis area in the control group compared with the sham group (p>0.05), no significant differences in the concentrations of serum NT-proBNP and TGF-β(p>0.05), and no significant differences in the expression of TGF-βand phosphorylated p38 in myocardial tissue (p>0.05) ;LVEF and LVFS were significantly decreased in MI group compared with control group (p <0.05), LVEDD, LVESD, LVEDV and LVESV data were significantly increased in four groups (p <0.05), plasma NT-proBNP and TGF-βconcentrations were significantly increased (p <0.05), inflammatory cell exudation and myocardial fibrosis were significantly increased (p <0.05), and the expression of TGF-βand phosphorylated p38 in myocardial tissue was significantly increased (p <0.05);LVEF and LVFS were significantly increased in the DAPA+MI group compared with the MI group (p <0.05), and the data of four groups, LVEDD, LVESD, LVEDV and LVESV, were significantly reduced (p <0.05), and plasma NT-proBNP, TGF-βconcentrations were significantly lower (p <0.05), inflammatory cell exudation and myocardial fibrosis were significantly lower (p <0.05), and the expression of TGF-βand phosphorylated p38 in myocardial tissue was significantly lower (p <0.05).
Conclusion: Dapagliflozin can improve ventricular remodeling after acute myocardial infarction in mice. Long-term administration of dapagliflozin can significantly improve the cardiac function of acute myocardial infarction mice, reduce left ventricular enlargement, inhibit myocardial fibrosis, and reduce infarct myocarditis. Symptomatic response, reducing myocardial cell necrosis and edema, reducing the infiltration of inflammatory cells, down-regulating the expression of TGF-β, and reducing the level of p38 phosphorylation. The above research results indicate that dapagliflozin can improve ventricular remodeling after acute myocardial infarction in mice, and this effect may be related to the reduction of TGF-βexpression and inhibition of p38 phosphorylation.|