Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism.
Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism.
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DOI：
10.1182/blood.v88.10.3894.bloodjournal88103894
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发表时间：
1996-11
期刊：
影响因子：
20.3
通讯作者：
T. Murohara;A. M. Lefer
中科院分区：
文献类型：
--
作者：
T. Murohara;A. M. Lefer
在体外研究了内皮素-1 （ET-1）对p选择素介导的白细胞内皮相互作用的影响。凝血酶（2 U/mL）、组胺（1 μ mol/L）或肉豆蔻酸酯（PMA）分别对内皮细胞进行刺激，可显著增强自体多形核白细胞（PMNs）对内皮细胞的粘附。相比之下，单独使用ET-1（10和100 nmol/L）仅能轻微增加粘附pmn的数量。经抗p -选择素单克隆抗体阻断的PMN对凝血酶或组胺刺激的内皮的粘附性增加，也可通过（100 nmol/L） ET-1预孵育冠状动脉段而显著减弱。我们进一步研究了ET-1抗粘附作用对凝血素刺激的内皮粘附的作用机制。冠状动脉段用选择性ETA受体拮抗剂BQ485 （1 μ mol/L）预孵育对ET-1抑制凝血素诱导的PMN粘附没有影响。相比之下，选择性ETB受体拮抗剂BQ788 （1 μ mol/L）的预孵育显著逆转了ET-1对凝血素诱导的PMN粘附的抑制作用，而选择性ETB受体激动剂BQ-3020模拟了ET-1对凝血素诱导的PMN粘附的抑制作用。此外，（100 μ mol/L） N ω -硝基-L-精氨酸甲酯（L- name），一种一氧化氮合酶（NOS）抑制剂，显著减弱ET-1对凝血酶刺激的PMN粘附的抑制作用。这些结果表明，ET-1可能通过刺激ETB受体抑制p选择素介导的白细胞与内皮细胞的相互作用和随后内皮细胞NO的形成。这种ET-1的自分泌作用可能参与病理生理状态，如通过阻止收缩血管中白细胞-内皮相互作用的早期动脉粥样硬化。
The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.