超声介导FGF21纳泡保护糖尿病小鼠心功能的研究

Ultrasound-assisted and Nanobubbles-mediated FGF21 Delivery Protect Cardiac Function in Diabetic Mice

目的研究应用纳泡结合超声技术介导成纤维细胞生长因子(fibroblast growth factor,FGF)21对糖尿病(diabetes mellitus,DM)小鼠心功能保护作用。方法采用双乳化法制备FGF21纳泡,并进行质量评价。48只雄性C57BL/6J小鼠随机选择40只小鼠经腹腔注射链脲佐菌素(streptozotocin,STZ)建立DM模型,其余作为对照组。将DM小鼠随机分为DM组、FGF21组、FGF21纳泡组和FGF21纳泡+超声组。各组分别给予相应干预8周后,行超声心动图检查,评价各组小鼠心脏收缩功能。处死小鼠取出心肌组织,行HE染色,天狼猩红染色检测心肌胶原容积分数(collagen volume fraction,CVF)。结果本研究制备的纳泡呈分散均匀、稳定的圆球形结构。经不同药物形式干预8周后,与对照组比较,DM组小鼠LVEF、LVFS显著降低(P<0.05);与DM组比较,FGF21组、FGF21纳泡+超声组小鼠LVEF、LVFS显著升高(P<0.05);与FGF21组比较,FGF21纳泡+超声组小鼠LVEF、LVFS显著升高(P<0.05);而FGF21纳泡组与DM组小鼠心脏功能指标比较,差异无统计学意义。HE染色和天狼星红染色显示,FGF21纳泡+超声组的心肌肥大程度和CVF显著低于DM组和其他药物治疗组(P<0.05)。结论载FGF21纳泡结合超声技术能够将FGF21高效、靶向递送到心肌组织,抑制心肌细胞肥大及间质纤维化,从而改善左心室收缩功能,发挥心脏保护作用。

Objective To investigate the protective effect of fibroblast growth factor(FGF)21 mediated by nanobubbles combined with ultrasound on the cardiac function of diabetic mice.Methods FGF21 nanobubbles were synthesized by a water/oil/water double-emulsion solvent evaporation method,and then their characterization was investigated.40 of 48 male C57BL/6J mice were randomly selected to establish diabetes mellitus(DM)model by intraperitoneal injection of streptozotocin(STZ),and the rest were used as control group.DM mice were randomly divided into DM group,FGF21 group,FGF21 nanobubbles group,and FGF21 nanobubbles+ultrasound group.After 8 weeks of treatment,cardiac function of mice in each group was evaluated by echocardiography.The mice were sacrificed and myocardium tissue was obtained for HE staining,and to quantify myocardium collagen volume fraction(CVF)by sirius red staining.Results The FGF21 nanobubbles were observed as uniform and stable spherical structure.After an 8-week intervention,the LVEF and LVFS of DM group were significantly decreased compared with those of control group(P<0.05).The LVEF and LVFS of FGF21 group and FGF21 nanobubbles+ultrasound group were significantly increased compared with those of DM group(P<0.05).The LVEF and LVFS of FGF21 nanobubbles+ultrasound group were significantly increased compared with those of FGF21 group(P<0.05).However,there was no significant difference in cardiac function between the FGF21 nanobubbles group and DM group.HE staining and sirius red staining showed that the degree of myocardial hypertrophy and CVF of FGF21 nanobubbles+ultrasound group were significantly decreased than those of DM group and other treatment groups(P<0.05).Conclusion FGF21 nanobubbles combining with ultrasound technique can deliver FGF21 to myocardial tissue efficiently,and improve left ventricular systolic function by inhibiting cardiomyocyte hypertrophy and interstitial fibrosis.