Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes
Potential Role of an Endothelium-Specific Growth Factor, Hepatocyte Growth Factor, on Endothelial Damage in Diabetes
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DOI：
10.2337/diab.46.1.138
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发表时间：
1997-01
期刊：
影响因子：
7.7
通讯作者：
R. Morishita;Shigefumi Nakamura;Y. Nakamura;M. Aoki;A. Moriguchi;I. Kida;Y. Yo;Kunio Matsumoto;Toshikazu Nakamura;J. Higaki;T. Ogihara
中科院分区：
文献类型：
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作者：
R. Morishita;Shigefumi Nakamura;Y. Nakamura;M. Aoki;A. Moriguchi;I. Kida;Y. Yo;Kunio Matsumoto;Toshikazu Nakamura;J. Higaki;T. Ogihara
已知内皮细胞分泌各种抗增殖和血管舒张因子。尽管内皮细胞损伤被认为是糖尿病患者动脉粥样硬化进展的初始触发因素，但糖尿病中内皮损伤的机制尚未阐明。因此，了解高葡萄糖对可能影响内皮细胞生长的因素的影响非常重要。内皮特异性生长因子的新成员肝细胞生长因子（HGF）是在血管细胞中产生的。为了研究高葡萄糖对血管细胞的影响，我们检查了 1) 高葡萄糖对内皮细胞和血管平滑肌细胞 (VSMC) 生长的影响以及 2) 高葡萄糖对内皮细胞和 VSMC 中局部 HGF 产生的影响。用高浓度的 D-葡萄糖（而不是甘露醇和 L-葡萄糖）处理人主动脉内皮细胞，导致细胞数量显着减少。有趣的是，添加重组 HGF 可以减弱高 D-葡萄糖诱导的内皮细胞死亡。因此，我们测量了内皮细胞的局部HGF分泌。重要的是，高 D-葡萄糖治疗显着降低了局部 HGF 的产生。相比之下，高 D-葡萄糖治疗导致人主动脉 VSMC 数量显着增加，而局部 HGF 产量则随着 D-葡萄糖浓度的增加而显着减少。在用高甘露醇和L-葡萄糖处理的VSMC中没有观察到数量上的显着变化。我们还研究了高 D-葡萄糖抑制局部 HGF 的机制。高 D-葡萄糖治疗刺激内皮细胞和 VSMC 中的转化生长因子-β (TGF-β) 浓度。通过添加抗 TGF-β 抗体消除了局部血管 HGF 产生的减少。由于 TGF-β 抑制内皮细胞和 VSMC 中局部 HGF 的产生，因此高 D-葡萄糖诱导的 TGF-β 增加可能会抑制局部 HGF 的产生。这项研究表明，高 D-葡萄糖诱导内皮细胞死亡，刺激 VSMC 生长，并通过刺激内皮细胞和 VSMC 中 TGF-β 的产生来减少局部 HGF 的产生。总体而言，高 D-葡萄糖导致的局部内皮刺激物 HGF 的减少可能是糖尿病中内皮损伤的触发因素，可能导致动脉粥样硬化的进展。
Endothelial cells are known to secrete various antiproliferative and vasodilating factors. Although injury of endothelial cells has been postulated as an initial trigger of the progression of atherosclerosis in patients with diabetes, the mechanisms of endothelial injury in diabetes are not yet clarified. Therefore, it is important to know the effects of high glucose on the factors that may influence endothelial cell growth. A novel member of endothelium-specific growth factors, hepatocyte growth factor (HGF), is produced in vascular cells. To investigate the effects of high glucose on vascular cells, we examined 1) the effects of high glucose on endothelial cell and vascular smooth muscle cell (VSMC) growth and 2) the effects of high glucose on local HGF production in endothelial cell and VSMC. Treatment of human aortic endothelial cell with a high concentration of D-glucose, but not mannitol and L-glucose, resulted in a significant decrease in cell number. Interestingly, addition of recombinant HGF attenuated high D-glucose–induced endothelial cell death. Therefore, we measured local HGF secretion of endothelial cell. Importantly, local HGF production was significantly decreased by high D-glucose treatment. In contrast, high D-glucose treatment resulted in a significant increase in the number of human aortic VSMCs, whereas local HGF production was significantly decreased in accordance with increase in D-glucose concentration. No significant changes in numbers were observed in VSMC treated with high mannitol and L-glucose. We also studied the mechanisms of local HGF suppression by high D-glucose. High D-glucose treatment stimulated transforming growth factor-β (TGF-β) concentration in endothelial cell and VSMC. Decreased local vascular HGF production was abolished by addition of anti-TGF-β antibody. As TGF-β inhibited local HGF production in endothelial cell and VSMC, increased TGF-β induced by high D-glucose may suppress local HGF production. This study demonstrated that high D-glucose induced endothelial cell death, stimulated VSMC growth, and decreased local HGF production through the stimulation of TGF-β production both in endothelial cell and VSMC. Overall, decrease in a local endothelial stimulant, HGF, by high D-glucose may be a trigger of endothelial injury in diabetes, potentially resulting in the progression of atherosclerosis.