van Leeuwen R T, Kol A, Andreotti F, Kluft C, Maseri A, Sperti G
Istituto di Cardiologia, Università Cattolica Del Sacro Cuore, Rome, Italy.
Circulation. 1994 Jul;90(1):362-8. doi: 10.1161/01.cir.90.1.362.
The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway.
The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity.
Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.
血管紧张素作为一种血管收缩剂的作用已得到充分证实。最近，人们认识到这种激素对血管平滑肌（VSM）细胞还有其他几种作用，包括诱导肥大和/或DNA合成。血小板衍生生长因子（PDGF）是一种有丝分裂原，最近显示可增加VSM细胞中纤溶酶原激活物抑制剂1型（PAI - 1）的合成，它与血管紧张素II（Ang II）在细胞内信号通路的几个步骤上有共同之处。
研究了培养的大鼠VSM细胞中PAI - 1和组织型纤溶酶原激活物（TPA）mRNA的表达。Northern印迹分析表明，用300 nmol/L Ang II刺激后3至8小时，PAI - 1 mRNA增加了几倍。观察到TPA mRNA有类似反应。这种诱导不需要合成中间蛋白质或肽，因为它不受放线菌酮的影响。在细胞条件培养基上清液中，加入300 nmol/L Ang II 6小时后，PAI - 1活性的净结果从4.18±1.8增加到13.2±6.8 IU/mL（平均值±标准差，P≤0.008，n = 6）。Ang II诱导的PAI活性增加与剂量相关，在浓度为23 nmol/L时达到最大效应（n = 3），半数有效剂量（ED50）为3.3±1.5 nmol/L（n = 3）。[Sar1 - Ile8]血管紧张素II是Ang II的特异性竞争性拮抗剂，可阻断10 nmol/L Ang II诱导的90±9%（n = 3）的PAI活性。在基础条件下，纤维蛋白覆盖酶谱法显示存在游离的TPA。用Ang II刺激后，TPA/PAI - 1复合物区域也出现了由TPA原位解离引起的溶解。血管紧张素I（Ang I）引起的PAI活性增加与等量剂量的Ang II相似。卡托普利（5微克/毫升）是一种血管紧张素转换酶（ACE）抑制剂，完全阻止了Ang I的作用，表明VSM细胞具有类似ACE的活性。
最近的研究表明存在局部血管肾素 - 血管紧张素系统。Ang II可能调节动脉壁纤溶酶原激活的这一发现，对于动脉壁血栓的演变以及动脉粥样硬化病变发生过程中细胞通过血管壁的迁移具有重要的生物学和治疗意义。我们推测，在既往心肌梗死患者以及用ACE抑制剂治疗的高肾素型高血压患者中观察到的血栓形成事件减少，至少部分可能是由于这些药物导致VSM细胞中PAI - 1产生减少所致。
