糖/血小板反应素-1/转化生长因子β_1信号传导途径在糖尿病心肌病发病中的作用

The role of glucose/TSP-1/TGFβ_1 signal pathways in diabetic cardiomyopathy

目的探讨糖/血小板反应素-1(TSP-1)/转化生长因子(TGF)β1信号传导途径在糖尿病心肌病发病中的作用。方法采用高脂高热量饮食诱导出胰岛素抵抗,加小剂量链脲佐菌素注射建立糖尿病心肌病动物模型,以Masson染色、实时定量逆转录-聚合酶链反应、Western blot技术,检测左室心肌胶原含量、TSP-1、TGFβ1mRNA和蛋白质表达水平的变化。结果与对照组相比,糖尿病心肌病大鼠左室心肌组织胶原含量明显高,存在心肌间质纤维化;TSP-1mRNA和蛋白质表达均明显高,TGFβ1mRNA、活性和非活性TGFβ1蛋白质表达亦明显高;TSP-1、TGFβ1mRNA水平与空腹血糖、心肌组织胶原含量以及左室舒张功能指标均明显相关,TSP-1、活性TGFβ1蛋白质表达水平与空腹血糖、心肌组织胶原含量以及左室舒张功能指标之间亦存在明显的相关关系,但非活性TGFβ1蛋白质表达水平与空腹血糖、心肌组织胶原含量以及左室舒张功能指标之间无相关性。结论糖/TSP-1/TGFβ1信号传导途径在糖尿病心肌病时心肌间质纤维化发生发展过程中可能起着重要的作用,为临床上糖尿病心肌病的治疗提供了新的靶点。

Objective Hyperglycemia could upregulate transforming growth factor-beta （TGFβ1） via thrombospondin （TSP-1） and induce fibrotic renal disease in the rat in vivo and myocardial fibrosis was related to cardiac dysfunction in diabetic patients. We explored the role of glucose/TSP-1/TGFI3t signal pathways in the development of diabetic cardiomyopathy （DCM）. Methods Male Wistar rats were fed with high cholesterol diet for 17 weeks, streptozocin （30 mg/kg, i, p） was given at the 28th day, rats with fasting blood glucose ≥11.1 mmol/L by the end of the 5th week were assiglned to DCM group （ n = 11 ）. Control rats （n =8） were fed with regular chow. Fasting blood glucose （FBG） was monitored throughout the study. After hemedynamic measurements by the end of the study, myocardial collagen content was quantified in Massen-stained samples and the mRNA expressions of TSP-1 and TGFI3t were detected by quantification realtime RT-PCR. The protein levels of TSP-1, active and latent TGFβ1 were detected by Western blot. Results Compared with control group, cardiac function was decreased as shown by significantly reduced left ventricular systolic pressure, dp/dtmax and dp/dtmin, while the myocardial collagen content was significantly increased in the DCM group（ 11.01 ± 3.05 vs. 16.92 ± 3.18, P 〈 0. 01 ）. The myocardial mRNA expressions of TSP-1, TGFβ1 and protein expressions of TSP-1, active and latent TGFβ1 in the DCM group were also significantly higher than those of the control group. Moreover, myocardial collagen was positively correlated to FBG （r=0. 746,P 〈0. 01） ; mRNA expressions of TSP-1 and TGFI3t, protein expressions of TSP-1 and active TGFβ1 were positively correlated to FBG and myocardial collagen （P 〈 0. 05）. However, there were no correlations between the protein expression of latent TGFI3t and FBG and myocardial collagen. Conclusion The pathway of glucose/TSP-1/TGFβ1 might play an important role in myocardial interstitial fibrosis of DCM. It may be the basis of novel therapeutic approaches for ameliorating DCM.