Resveratrol improves bone marrow mesenchymal stem cells by down-regulating microRNA-34a in the treatment of diabetic rats with myocardial infarction

Objective To verify that resveratrol (RSV) can reduce the senescence of bone marrow mesenchymal stem cells (BMSCs) under high glucose conditions by regulating miR-34a, thereby improving the effect of BMSCs transplantation in the treatment of diabetes mellitus (DM) with myocardial infarction (MI). Methods In cell experiments,BMSCs were isolated from 3-week-old male SD rats and were divided into 8 groups: group A, low glucose (LG) group (containing 5.5 mmol/L of glucose); group B, high glucose (HG) group (containing 25 mmol/L of glucose); group C, HG+miR-34a mimic group; group D, HG+miR-34a normal control (NC) group; group E, HG+miR-34a inhibitor group; group F, HG+RSV group; group G, HG+RSV+miR-34a mimic group; group H, HG+RSV+miR-34a inhibitor group. The expression of miR-34a was detected by quantitative reverse transcription PCR (RT-qPCR). Western blot was used to detect the expression of P21 and P16 protein. Senescence-associated β-galactosidase assay was used to detect the senescence level of each group. In vivo experiments, 200 g male SD rats were fed with high-fat and high-sugar feed and were injected with STZ to induce type 2 diabetes model, and then coronary artery ligation method was used to establish a model of diabetes combined with myocardial infarction, which was divided into 6 groups: DM group (diabetes group), DM+sham group, DM+MI group, DM+MI+LG group (low glucose BMSCs injection group), DM+MI+HG group (high glucose BMSCs injection group), DM+MI+RSV group (HG group after RSV pretreatment). Each group was injected with differently treated BMSCs after MI. Echocardiography was used to detect the cardiac function at 1 week and 3 weeks after operation. Results Compared with the LG group, the expression of miR-34a increased in the HG group (P<0.01), and the level of cellular senescence increased (P<0.01). Compared with the HG group, the expression of miR-34a decreased in the HG+RSV group (P<0.01), and the level of cellular senescence was reduced (P<0.01). After RSV pretreatment, no matter miR-34a was overexpressed or inhibited, the expression of P21 and P16 protein decreased (P<0.01 or P<0.05). After RSV pretreatment, the expression of P21 and P16 can be reduced whether miR-34a is overexpressed or inhibited (P<0.01 or P<0.05). Echocardiographic results showed that compared with the DM group, the postoperative left ventricular ejection fraction (LVEF) values of the DM+MI group, DM+MI+LG group, DM+MI+HG group, and DM+MI+RSV group all decreased (P<0.01). Compared with DM+MI group, postoperative LVEF values of the DM+MI+LG group, DM+MI+HG group, DM+MI+RSV group increased (P<0.01 or P<0.05). Compared with DM+MI+HG group, postoperative LVEF values of the DM+MI+RSV group and DM+MI+LG group increased (P<0.01 or P<0.05). Conclusions RSV pretreatment of BMSCs can reduce the senescence level of BMSCs under high glucose conditions by reducing miR-34a, and can optimize the therapeutic effect of BMSCs on diabetes with myocardial infarction.