RESUMEN
Objective:To explore if protective effects of dapagliflozin (Dapa) administration on attenuating DOX-induced myocardial injury in rats.Methods:A total of 30 specific pathogens free grade 8 week old male Sprague Dawley rats. Rats were randomly divided into three groups. Control group (Con group, n = 5), rats received intraperitoneal saline (1.25 ml/kg) injection once per week plus saline (8 mg/kg) daily via gavage for 6 weeks. Dox group ( n = 15) rats received intraperitoneal Dox (2.5 mg/kg) injection once per week plus saline (8 mg/kg) daily via gavage for 6 weeks. Dox + Dapa group ( n = 10), rats received intraperitoneal Dox (2.5 mg/kg) injection once per week plus Dapagliflozin (4 mg/kg) daily via gavage for 6 weeks, observed to week 10. Survival status, echocardiography, pathology, and expression of Bcl-2, Bax gene and protein were observed. Results:The survival rate of ats in Con, Dox, and Dapa+Dox groups was 100.0%, 66.7% and 90.0% respectively. The echocardiography were performed in Con, Dox, and Dapa+Dox groups left ventricular ejection fraction was (95.40 ± 2.51)%, (83.09 ± 4.92)% and (91.71 ± 3.45)%, respectively; left ventricular fraction shortening was (66.80 ± 7.43)%, (47.27 ± 5.10)% and (59.43 ± 6.92)%, respectively; Both indexes in Dapa+Dox group was higher than that in Dox group, but lower than that in Con group, all P<0.05; Left ventricular end-diastolic diameter was (4.80 ± 0.83) mm, (5.90 ± 0.83) mm and (4.85 ± 0.69) mm respectively; left ventricular end-systolic diameterwas (1.80 ± 0.44) mm, (2.90 ± 0.53) mm and (2.00 ± 0.57) mm in Con, Dox, and Dapa + Dox groups, respectively; Both indexes in Dapa + Dox group was decreased than that in Dox group, but Dapa + Dox group was increased than that in Con group, all P<0.05. Pathologic changes have been shown that myocardial fibers arranged neatly in the Con group under HE staining, while those broken myocardial fibers disordered arranged in the Dox group, and those changes in the Dapa + Dox group were slightly relieved than that in Dox group. The collagen volume fraction of rats in Con, Dox and Dapa+Dox groups were (2.64 ± 1.04)%, (16.85 ± 1.70)% and (6.75 ± 1.89)% under sirius red staining, Dapa+Dox group was lower than that in Dox group but higher than that in Con group, all P<0.05. Pathologic changes under transmission electron microscope have been shown that a few of normal structure mitochondria in the Con group. A large number of swollen mitochondria with disappeared mitochondrial crest in the Dox group; but neatly arranged with mitochondrial crest blurred in the Dapa+Dox group. The quantitative real-time PCR was used to detected Bcl-2 and Bax, there were 0.93 ± 0.09, 0.35 ± 0.30 and 0.89 ± 0.25 in Bcl-2, 0.99 ± 0.10, 3.10 ± 0.10 and 0.86 ± 0.04) in Bax, while Bcl-2/Bax 0.94 ± 0.17, 0.11 ± 0.06 and 1.03 ± 0.27, respectively. The westernblot was used to detected Bcl-2 and Bax, there were 1.00 ± 0.18, 0.32 ± 0.20 and 1.30 ± 0.41 in Bcl-2, 0.66 ± 0.11, 2.44 ± 0.66 and 0.90 ± 0.61 in Bax, while Bcl-2/Bax: 1.50 ± 0.18, 0.12 ± 0.05 and 1.80 ± 0.82, respectively; the above results shown that both myocardial Bax mRNA and protein expression in Dox group were higher than that in Dapa + Dox group and Con group, both P<0.05, and there was no difference in the two later groups, P>0.05; both the myocardial Bcl-2 mRNA and protein expression in Dox group were lower than that in Dapa+Dox group and Con group, both P<0.05, and there was no difference between two later groups, P>0.05; Bcl-2/Bax in Dox group was significantly lower thanthat in Dapa+Dox groupand Con group, both P<0.05, and there was no difference between Dapa+Dox group and Con group, P>0.05. Conclusions:Simultaneous dapagliflozin treatment significantly attenuated DOX-induced cardiotoxicity, which might be related to prevent myocardial apoptosis.
