Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy
Neuregulin-1 Promotes Myocardial Angiogenesis in the Rat Model of Diabetic Cardiomyopathy
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Neuregulin-1 促进糖尿病心肌病大鼠模型中的心肌血管生成
DOI：
10.1159/000489622
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Chen, Lin-lin
中科院分区：
文献类型：
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作者：
Gui, Chun;Zeng, Zhi-yu;Chen, Lin-lin
背景/目的：微血管功能不全在糖尿病性心肌病（DCM）的发展中起着关键作用。本研究旨在探讨Neuregulin-1（NRG-1）对扩张型心肌病大鼠心肌血管生成的影响及VEGF/Flk 1和Ang-1/Tie-2信号通路的变化。方法：采用链脲佐菌素腹腔注射诱导糖尿病大鼠模型。糖尿病诱导12周后，给予NRG-1治疗的大鼠尾静脉注射NRG-1，剂量为10µg/kg/d，连续10天。心功能测定采用心导管MPA心功能分析系统。用稳定同位素标记微球测定心肌血流量。CD 31免疫组化法检测毛细血管密度。蛋白质印迹法检测蛋白质表达和受体磷酸化水平。结果如下：与对照组比较，DCM组左室功能、毛细血管密度和MBF均显著降低（P< 0.01，P< 0.01和P< 0.05）。与DCM组比较，NRG-1治疗组左心功能和毛细血管密度均显著增加（P< 0.05和P< 0.05）。DCM组VEGF、Ang-1的表达及Flk 1、Tie-1的磷酸化水平较对照组明显降低。然而，与DCM组相比，NRG-1治疗组中的那些显著增加。在体外，NRG-1处理显著增加人冠状动脉平滑肌细胞中VEGF和Ang-1的表达。结论：NRG-1可促进DCM心肌血管生成，其机制可能与NRG-1的直接作用及增加VEGF和Ang-1的表达有关。这些发现可能有助于开发一种新的方法来逆转糖尿病或冠状动脉疾病中受损的血管生成反应。
Background/Aims: Microvascular insufficiency takes a critical role in the development of diabetic cardiomyopathy (DCM). So this study was designed to investigate the effects of Neuregulin-1 (NRG-1) treatment on myocardial angiogenesis and the changes of VEGF/Flk1 and Ang-1/Tie-2 signaling in the rat model of DCM. Methods: Diabetic rats were induced by a single intraperitoneal injection of Streptozotocin. 12 weeks after the diabetes induction, the rats with NRG-1 treatment were treated with tail vein injection of NRG-1 at the dose of 10µg/kg/d for consecutive 10 days. Cardiac function was assessed using catheter MPA cardiac function analysis system. Myocardial blood flow (MBF) was assessed with stable-isotope labeled microspheres. Capillary density was measured by CD31 immunohistochemistry. The protein expression and receptors phosphorylation were assessed using western blot. Results: Left ventricular function, capillary density and MBF were significantly reduced in DCM group when compared with those in the control group (P< 0.01, P< 0.01 and P< 0.05 respectively). Left ventricular function and capillary density were significantly increased in NRG-1 treatment group when compared with those in the DCM group (P< 0.05 and P< 0.05 respectively). The expression of VEGF and Ang-1 and the phosphorylation of Flk1 and Tie-1 were significantly decreased in DCM group as compared with those in the control group. However, those in the NRG-1 treatment group were significantly increased as compared with those in the DCM group. In vitro, NRG-1 treatment increased significantly the expression of VEGF and Ang-1 in human coronary artery smooth muscle cells. Conclusions: NRG-1 can increase the myocardial angiogenesis of DCM, probably via the direct effects of NRG-1 and via the increasing expression of VEGF and Ang-1. These findings may contribute to developing a novel approach to reverse the impaired angiogenic responses in diabetes or coronary artery disease.