Lauth M, Cattaruzza M, Hecker M
Department of Cardiovascular Physiology, University of Göttingen, Göttingen, Germany.
Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):61-6. doi: 10.1161/01.atv.21.1.61.
Deformation-induced endothelin-1 synthesis in endothelial cells may contribute to the intimal hyperplasia of venous bypass grafts. ACE inhibitors and angiotensin II type 1 (AT(1)) receptor antagonists are capable of reducing vein graft disease. Therefore, the effects of these drugs on endothelial preproendothelin-1 (ppET-1) and smooth muscle endothelin B receptor (ET(B)-R) expression were investigated in isolated perfused segments of the rabbit jugular vein. Pretreatment with ramiprilat (0.3 micromol/L) or irbesartan (0.01 to 1 micromol/L) had no effect on basal ppET-1 or ET(B)-R expression but markedly attenuated the deformation-induced expression of these gene products, and these effects were reversed by the B(2) receptor antagonist icatibant (Hoe 140) and by the NO synthase inhibitor N(G)-nitro-L-arginine. Candesartan (1 micromol/L) mimicked the inhibitory effect of irbesartan. Moreover, reporter gene analysis with a rat ppET-1 promoter-luciferase construct transiently transfected into porcine aortic cultured endothelial cells revealed that the inhibitory effect of both ramiprilat and irbesartan on deformation-induced ppET-1 expression is species independent and mediated at the level of transcription. In addition, RT-PCR analysis detected only AT(1) receptor expression in the endothelium-intact rabbit jugular vein, and neither irbesartan nor ramiprilat affected endothelial NO synthase expression. Thus, ACE inhibitors and AT(1) receptor antagonists are capable of suppressing deformation-induced gene expression in the vessel wall in both an autocrine (ppET-1) and a paracrine (ET(B)-R) manner via a common mechanism of action that constitutes a B(2) receptor-mediated increase in endothelial NO release.
内皮细胞中变形诱导的内皮素-1合成可能导致静脉搭桥移植物的内膜增生。血管紧张素转换酶（ACE）抑制剂和血管紧张素II 1型（AT(1)）受体拮抗剂能够减轻静脉移植物病变。因此，在兔颈静脉离体灌注段中研究了这些药物对内皮前内皮素-1（ppET-1）和平滑肌内皮素B受体（ET(B)-R）表达的影响。用雷米普利拉（0.3 μmol/L）或厄贝沙坦（0.01至1 μmol/L）预处理对基础ppET-1或ET(B)-R表达无影响，但显著减弱了变形诱导的这些基因产物的表达，并且这些作用被B(2)受体拮抗剂艾替班特（Hoe 140）和一氧化氮合酶抑制剂N(G)-硝基-L-精氨酸逆转。坎地沙坦（1 μmol/L）模拟了厄贝沙坦的抑制作用。此外，用瞬时转染到猪主动脉培养内皮细胞中的大鼠ppET-1启动子-荧光素酶构建体进行的报告基因分析表明，雷米普利拉和厄贝沙坦对变形诱导的ppET-1表达的抑制作用与物种无关，且在转录水平介导。另外，逆转录-聚合酶链反应（RT-PCR）分析仅在完整内皮的兔颈静脉中检测到AT(1)受体表达，并且厄贝沙坦和雷米普利拉均不影响内皮型一氧化氮合酶表达。因此，ACE抑制剂和AT(1)受体拮抗剂能够通过一种共同的作用机制以自分泌（ppET-1）和旁分泌（ET(B)-R）方式抑制血管壁中变形诱导的基因表达，该机制构成了B(2)受体介导的内皮一氧化氮释放增加。
