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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >A sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin comparison with insulin shows important effects on Zn2+-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress
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A sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin comparison with insulin shows important effects on Zn2+-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress

机译：与胰岛素的钠 - 葡萄糖COT转折剂2（SGLT2）抑制剂Dapagliflozin与胰岛素的比较显示了通过抑制氧化应激的胰岛素抗性代谢综合征大鼠的心肌细胞中的Zn2 + -trangepors的重要作用

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Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed significant effects in patients with diabetes or metabolic syndrome (MetS) with high cardiovascular risk. Although the increased intracellular Zn2+ level ([Zn2+](i)), oxidative stress, and altered cardiac matrix metalloproteinases (MMPs) in diabetic cardiomyopathy can intersect with different signaling pathways, the exact mechanisms are not known yet. Since either MMPs or SGLT2 have important roles in cardiac-fibrosis under hyperglycemia, we aimed to examine the role of SGLT2 inhibitor dapagliflozin (DAP) on cardiac Zn2+-transporters responsible for [Zn2+](i)-regulation, comparison to insulin (INS), together with MMP levels and systemic oxidative stress status in MetS-rats. High-carbohydrated diet-induced MetS-rats received DAP or INS for 2 weeks. DAP but not INS in MetS-rats significantly decreased high blood-glucose levels, while both treatments exerted benefits on increased total oxidative status and decreased total antioxidant status in MetS-rat plasma as well as in heart tissue. Protein levels of Zn2+-transporters, responsible for Zn2+-influx into cytosol, ZIP7 and ZIP14 were increased with significant decrease in ZIP8 of MetS-rat cardiomyoctes, while Zn2+-transporters, responsible for cytosolic Zn2+-efflux, ZnT7 was decreased with no change in ZnT8. Both treatments induced significant beneficial effects on altered ZIP14, ZIP8, and ZnT7 levels. Furthermore, both treatments exerted benefits on depressed gelatin-zymography and protein expression levels of MMP-2 and MMP-9 in MetS-rat ventricular cardiomyocytes. The direct effect of DAP on heart was also confirmed with measurements of left ventricular developed pressure. Overall, we showed that DAP has important antioxidant-like cardio-protective effects in MetS-rats, similar to INS-effect, affecting Zn2+-regulation via Zn2+-transporters, MMPs, and oxidative stress. Therefore one can suggest that SGLT2 inhibitors can be new therapeutic agents for cardio-protection not only in hyperglycemia but also in failing heart.
机译：葡萄糖COTRANSPORTER 2（SGLT2）抑制剂对糖尿病或代谢综合征（METS）患者具有显着的患者，具有高心血管风险。虽然糖尿病心肌病中的增加的细胞内Zn2 +水平（[Zn2 +]（I）），氧化应激和改变的心脏基质金属蛋白酶（MMP）可以与不同的信号通路相交，但尚未知道确切的机制。由于MMP或SGLT2在高血糖症下的心脏纤维化中具有重要作用，我们旨在研究SGLT2抑制剂Dapagliflozin（DAP）对负责[Zn2 +]（I）的心脏Zn2 + -Trangherers的作用 - 与胰岛素（INS）的比较，与METS-RAT的MMP水平和全身氧化应激状态。高碳水化合物诱导的Mets-rats接受了2周的DAP或INS。 DAP但在Metbor大鼠中没有INS显着降低了高血糖水平，而这两种治疗方法都会施加有益于总氧化状态，并且降低了Mets-大鼠血浆以及心脏组织中的总抗氧化状态。 Zn2 + -Oranghers的蛋白质水平，负责Zn2 + -Influx进入细胞溶溶胶，ZIP7和ZIP14的ZIP7和ZIP14的ZIP8的显着降低，而Zn2 + -Trangepers负责细胞源Zn2 + -Ufflux，ZnT7的ZnT7没有变化ZnT8。这两种治疗诱导对改变的ZIP14，ZIP8和ZnT7水平的显着有益效果。此外，这两种治疗都对METS-rat-renticurecy细胞的MMP-2和MMP-9的抑制明胶 - 酶谱和蛋白表达水平施加了益处。 DAP对心脏的直接作用也被左心室发育压力的测量结果证实。总体而言，我们表明，DAP在METS-RAT中具有重要的抗氧化剂类心脏保护作用，类似于通过Zn2 + -Tranghers，MMP和氧化应激影响Zn2 + -regulation。因此，人们可以表明SGLT2抑制剂可以是新的治疗剂，用于心血管保护，不仅在高血糖症中，还可以在失败的心脏中。

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