Reantragoon S, Arrigo L M, Seoud M M, Dweck H S, Rosenfeld L
Department of Pediatrics, New York Medical College, Valhalla 10595.
Arch Biochem Biophys. 1994 Nov 1;314(2):315-22. doi: 10.1006/abbi.1994.1448.
Vascular endothelial cells produce endothelin-1, a peptide with potent vasoconstrictor and mitogenic properties. Heparin suppresses thrombin-stimulated endothelin-1 production in endothelial cells; this is consistent with its reported effect of lowering blood pressure. Since heparin is a heterogeneous mixture of glycosaminoglycans, we examined the effects of different fractions of heparin in suppressing endothelin-1 production in cultured endothelial cells. Heparin fractions differing in size and in antithrombin III affinity were prepared. The results show that the suppressive effect of heparin is independent of these properties of size and antithrombin III affinity. Heparin sulfate suppressed endothelin-1 production to a similar level as heparin. These experiments were conducted in a complete culture medium in the absence of added thrombin. To assess the role of endogenous thrombin in the medium on this process, we tested the effects of hirudin, a specific thrombin inhibitor peptide, on suppression of endothelin-1. Hirudin, like heparin, binds to the anion-binding exosite of thrombin. Hirudin alone, and combined with heparin, suppressed endothelin levels to the same extent as heparin. These experiments demonstrate that the suppressive effect of heparin is the result of its binding to the traces of thrombin in the culture medium, preventing stimulation of endothelin-1 production. This study supports the hypothesis that the functional thrombin receptor may participate in the stimulation of endothelin-1 by thrombin.
血管内皮细胞产生内皮素 -1，这是一种具有强大血管收缩和促有丝分裂特性的肽。肝素可抑制凝血酶刺激的内皮细胞中内皮素 -1的产生；这与其报道的降低血压的作用相一致。由于肝素是糖胺聚糖的异质混合物，我们研究了不同肝素组分对培养的内皮细胞中内皮素 -1产生的抑制作用。制备了大小和抗凝血酶 III 亲和力不同的肝素组分。结果表明，肝素的抑制作用与大小和抗凝血酶 III 亲和力这些特性无关。硫酸肝素对内皮素 -1产生的抑制程度与肝素相似。这些实验是在无添加凝血酶的完全培养基中进行的。为了评估培养基中内源性凝血酶在此过程中的作用，我们测试了水蛭素（一种特异性凝血酶抑制肽）对内皮素 -1抑制作用的影响。水蛭素与肝素一样，与凝血酶的阴离子结合外位点结合。单独使用水蛭素以及与肝素联合使用时，对内皮素水平的抑制程度与肝素相同。这些实验表明，肝素的抑制作用是其与培养基中微量凝血酶结合的结果，从而防止了对内皮素 -1产生的刺激。本研究支持功能性凝血酶受体可能参与凝血酶对内皮素 -1刺激的假说。
