达格列净降低心力衰竭大鼠心肌内质网应激并缓解左室重构

Dapagliflozin decreases myocardial endoplasmic reticulum stress and relieves left ventricular remodeling in rats with heart failure

目的观察达格列净对心力衰竭大鼠心肌细胞内质网应激(ERS)的影响,并探讨其与左室重构的关系。方法将大鼠分为对照组、模型组(行主动脉缩窄术,TAC)和达格列净干预组(每日1次灌胃给予达格列净0.5和1.0 mg/kg)。用无创大鼠尾动脉测压仪检测平均动脉压(MAP);称取体质量、全心质量及左心室质量计算大鼠心肌肥厚指数HWI及LVWI;HE染色观察心肌细胞形态学改变;免疫组化及Western blot检测心肌组织中GRP78及CHOP表达水平。超声检测大鼠心功能指标射血分数(EF)及左心室短轴率(FS)。结果1)与对照组相比,模型组大鼠MAP、HWI、LVWI显著升高(P<0.01),EF及FS值显著降低(P<0.01)。与模型组相比,达格列净干预组HWI、LVWI明显降低(P<0.05),EF及FS值明显升高(P<0.05)。2)模型组大鼠心肌纤维排除紊乱,形态不规则,组织疏散;达格列净干预组大鼠心肌纤维排列紊乱及组织疏散较模型组好转,细胞形态规则。3)与对照组相比,模型组心肌GRP78、CHOP蛋白表达显著增高(P<0.01);与模型组相比,达格列净干预组GRP78、CHOP表达明显降低(P<0.05)。结论达格列净明显抑制心肌细胞ERS,下调GRP78及CHOP表达,保护心肌细胞,有效缓解心室重构及改善心脏功能;ERS可能是达格列净改善心力衰竭的潜在分子机制之一。

Objective To observe the influence of dapagliflozin on ERS of myocardial tissues from rats with heart failure,and explore the its relationship with myocardial remodeling.Methods The rats were divided into the control group,model group(with aortic coarctation,TAC)and Dapagliflozin intervention group(with Dapagliflozin 0.5 and 1.0 mg/kg given by gavage once daily).Non-invasive rat tail artery manometer was used to detect mean arterial pressure.Weigh body weight,whole heart weight and left ventricular weight were recorded to calculate the rat myocardial hypertrophy index HWI and LVWI.Small animal ultrasound was used to detect rat heart function.The morphological changes of cardiomyocytes was microscopied with HE staining.Immuno-histochemistry and Western blot were used to detect GRP78 and CHOP expression in rat myocardial tissue.ResultsCompared with the control group,MAP,HWI and LVWI in the model group were significantly increased(P<0.01),EF and FS decreased significantly(P<0.01).Compared with the model group,HWI and LVWI were reduced(P<0.05),EF and FS were increased(P<0.05)in dapagliflozin group.HE staining showed that the myocardial fibers in control group were neatly arranged and morphologically regular;in model group,the myocardial fibers were excluded from the disorder,the morphology was irregular,and the tissue was evacuated;the myocardial fibers in dapagliflozin group were better than that of model group.Compared with control group,the expression of GRP78 and CHOP in the myocardium of model group was significantly increased(P<0.01);compared with model group,the expression of GRP78 and CHOP in dapagliflozin group was reduced(P<0.05).Conclusions Dapagliflozin obviously inhibits ERS,down-regulates the expression of GRP78 and CHOP,protects cardiomyocytes,more effectively relieves ventricular remodeling and improves cardiac function.ERS may be one of the molecular biological mechanisms of Dapagliflozin.