Comparative evaluation of the possible effects of linagliptin and empagliflozin treatments on STZ-diabetic rat HEART in terms of mirnas

DPP-4 and SGLT2 inhibitors have frequently been used for the treatment of type 2 diabetes in recent years. Preclinical and clinical studies stand out the cardiovascular benefit of both groups. miRNAs are non-coding small RNAs that regulate many body functions through their target mRNAs. Recent studies have suggested that some drugs exert their effects by modulating specific miRNAs. Based on this information, we aimed to investigate the cardiac effect of linagliptin, a DPP-4 inhibitor, and empagliflozin, an SGLT2 inhibitor, through their relationship with miRNAs in STZ diabetic rat model. For this purpose, rats were randomly divided into six groups as follows; control, diabetic, linagliptin treated control, linagliptin treated diabetic, empagliflozin treated control and empagliflozin treated diabetic. Diabetes was induced by STZ injection (50 mg/kg), and after 12-15 weeks of diabetes, linagliptin (4mg/kg/day) or empagliflozin (30mg/kg/day) was administered for 8-10 weeks to treated groups. In vivo cardiac function was evaluated by echocardiography before and at the 8th week of the treatment. After that, in vitro β-adrenergic responsiveness was evaluated in papillary muscle and Ca+2 measurement/imaging was performed in isolated cardiomyocytes. miRNAs (miR-221, miR-212, miR-29b, miR-29a, miR-199a, miR-30a, miR-1, miR-133a, miR-125b, miR-21, miR-373) were scanned in frozen left ventricular tissues. Then, the target genes of the miRNAs which are significantly changed were identified by using special programs. mRNA and protein expressions of these genes were measured. Data were expressed as mean ± SD. For paired comparisons t-test, for multiple comparisons one-way ANOVA followed by Tukey post-hoc test were performed. p<0.05 was considered as statistically significant. In conclusion, STZ induced diabetes-related hypertrophy was confirmed by an increase in heart weight/body weight ratio and some echocardiographic parameters. The β-AR-mediated contractile response induced by isoprenaline and β1- and β2-AR mRNA expressions were comparable among groups. miR-1 and miR-133a expressions were decreased in all groups compared to control. The mRNA and protein expressions of PLN, NCX and PRKACB which are the targets of these miRNAs did not differ between groups. SERCA2a protein expression was decreased in diabetic and treated diabetics compared to control. In the light of these results, it was found that neither empagliflozin nor linagliptin exerts a beneficial effect on functional or molecular changes seen in STZ diabetic rat heart. To test the positive effects of both drug in the diabetic heart, future studies which use a different diabetic model or prefer a "prevention" instead of "treatment" approach may help.