Zhong Ming, Zhang Wei, Miao Ya, Ma Xiao, Gong Hui-ping, Sun Hui, Tang Meng-xiong, Zhang Yun
Department of Cardiology, Qilu Hospital of Shandong University, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Public Health, Jinan 250012, China.
Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Mar;34(3):217-21.
Hyperglycemia could upregulate transforming growth factor-beta (TGFbeta(1)) 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/TGFbeta(1) signal pathways in the development of diabetic cardiomyopathy (DCM).
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 > or = 11.1 mmol/L by the end of the 5th week were assigned to DCM group (n = 11). Control rats (n = 8) were fed with regular chow. Fasting blood glucose (FBG) was monitored throughout the study. After hemodynamic measurements by the end of the study, myocardial collagen content was quantified in Masson-stained samples and the mRNA expressions of TSP-1 and TGFbeta(1) were detected by quantification real-time RT-PCR. The protein levels of TSP-1, active and latent TGFbeta(1) were detected by Western blot.
Compared with control group, cardiac function was decreased as shown by significantly reduced left ventricular systolic pressure, dp/dt(max) and dp/dt(min), 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, TGFbeta(1) and protein expressions of TSP-1, active and latent TGFbeta(1) 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 TGFbeta(1), protein expressions of TSP-1 and active TGFbeta(1) were positively correlated to FBG and myocardial collagen (P < 0.05). However, there were no correlations between the protein expression of latent TGFbeta(1) and FBG and myocardial collagen.
The pathway of glucose/TSP-1/TGFbeta(1) might play an important role in myocardial interstitial fibrosis of DCM. It may be the basis of novel therapeutic approaches for ameliorating DCM.
高血糖可通过血小板反应蛋白（TSP-1）上调转化生长因子-β（TGFβ1），并在大鼠体内诱发肾纤维化疾病，且心肌纤维化与糖尿病患者的心脏功能障碍有关。我们探讨了葡萄糖/TSP-1/TGFβ1信号通路在糖尿病性心肌病（DCM）发展中的作用。
雄性Wistar大鼠喂以高胆固醇饮食17周，在第28天腹腔注射链脲佐菌素（30 mg/kg），第5周结束时空腹血糖≥11.1 mmol/L的大鼠被分配至DCM组（n = 11）。对照大鼠（n = 8）喂以常规饲料。在整个研究过程中监测空腹血糖（FBG）。研究结束时进行血流动力学测量后，对Masson染色样本中的心肌胶原含量进行定量，并通过定量实时RT-PCR检测TSP-1和TGFβ1的mRNA表达。通过蛋白质印迹法检测TSP-1、活性和潜伏性TGFβ1的蛋白水平。
与对照组相比，DCM组心脏功能下降，表现为左心室收缩压、dp/dt（max）和dp/dt（min）显著降低，而心肌胶原含量显著增加（11.01±3.05对16.92±3.18，P < 0.01）。DCM组心肌中TSP-1、TGFβ1的mRNA表达以及TSP-1、活性和潜伏性TGFβ1的蛋白表达也显著高于对照组。此外，心肌胶原与FBG呈正相关（r = 0.746，P < 0.01）；TSP-1和TGFβ1的mRNA表达、TSP-1和活性TGFβ1的蛋白表达与FBG及心肌胶原呈正相关（P < 0.05）。然而，潜伏性TGFβ1的蛋白表达与FBG及心肌胶原之间无相关性。
葡萄糖/TSP-1/TGFβ1通路可能在DCM的心肌间质纤维化中起重要作用。它可能是改善DCM新治疗方法的基础。
