A novel vasoactive peptide, 31-amino acid length endothelin, by human chymase and its relation to atherosclerosis

人糜酶产生新的内皮素-1，其具有31个氨基酸长度ET-1（1-31），其比常规ET-1，ET-1（1-21）长。本研究旨在探讨内皮素-1（1-31）对猪冠状动脉血管平滑肌细胞（VSMC）的作用。ETA受体拮抗剂BQ 485完全阻断ET-1（1-31）的收缩作用，而ETB受体拮抗剂BQ 788则略有增强作用，提示ET-1（1-31）通过内皮舒张动脉。在内皮细胞上，ET-1（1-21）和ET-1（1-31）增加[Ca ~（2+）]i和产生NO，这两种作用均被BQ 788显著抑制，而BQ 485不抑制。结果表明，ET-1（1-31）与ET-1（1-21）相似，通过ETB受体增加内皮细胞[Ca ~（2+）]i，产生NO。尽管ET-1（1-31）对[Ca（2+）]（i）的增加和动脉收缩作用比ET-1（1-21）弱10倍，但ET-1（1-31）对VSMC增殖、c-fos/c-myc mRNA表达和细胞周期分析的作用与ET-1（1-21）相当。ET-1（1-31）可诱导cyclin D1的表达，但对cyclin D2和D3的表达无明显影响。这些作用被BQ 485特异性抑制。这些结果表明，ET-1（1-31）也可以参与VSMC增殖过程，如动脉粥样硬化。

Human chymase produces a novel endothelin-1 with 31 amino-acid length ET-1 (1-31), which is longer than conventional ET-1, ET-1 (1-21). The aim of our study was to investigate the role of ET-1 (1-31) on porcine coronary vascular smooth muscle cell (VSMC). BQ485, an ETA receptor antagonist, completely abolished ET-1 (1-31)-induced contraction, but BQ788, an ETB receptor antagonist, slightly enhanced it, suggesting that ET-1 (1-31) relaxes artery via endothelium. On endothelial cells, ET-1 (1-21) and ET-1 (1-31) increased [Ca2+]i and produced NO, both of which were significantly inhibited by BQ788 and not by BQ485. These results indicate that ET-1 (1-31) increased [Ca2+]i and produced NO in endothelial cells through ETB receptor similarly with ET-1 (1-21). Although the increase in [Ca(2+)](i) by ET-1 (1-31) and contraction of artery was 10 times weaker than that of ET-1 (1-21), ET-1 (1-31) showed equivalent potency in VSMC proliferation, c-fos/c-myc mRNA expression and cell cycle analysis with ET-1 (1-21). ET-1 (1-31) significantly induced expression of cyclin D1 but not those of cyclin D2 or D3. These effects were specifically inhibited by BQ485. These results indicate that ET-1 (1-31) also can involve a VSMC proliferation process such as atherosclerosis.