Angiotensin converting enzyme (ACE): defining its role as a signal transduction molecule

血管紧张素转化酶（ACE）在内皮细胞中表达，并催化血管紧张素I转化为血管收缩剂血管紧张素II以及降解强效血管扩张剂缓激肽。ACE在几种心血管疾病状态的发展中起核心作用，并且可以在心血管疾病进展期间在非内皮细胞中诱导。ACE抑制剂对人类受试者以及各种动物模型中观察到的心血管疾病进展的保护作用最好地说明了ACE在调节血管功能和体内平衡中的重要性。然而，ACE抑制剂的一些明显有益作用不能归因于抑制血管紧张素II的产生或防止缓激肽降解。在过去的两年中，我们已经收集了有趣的新证据表明，ACE是一种信号转导分子，它参与了由外向内的信号转导，因为ACE底物或ACE抑制剂与ACE的结合能够引发细胞内事件。本研究计划的目的是：1）阐明ACE信号影响的细胞内事件以及其激活的生理后果和2）阐明决定内皮细胞中ACE表达的因素和刺激，并因此可能影响下游信号。

The angiotensin converting enzyme (ACE) is expressed in endothelial cells and catalyses the conversion of angiotensin I to the vasoconstrictor angiotensin II as well as the degradation of the potent vasodilator bradykinin. ACE plays a central role in the development of several cardiovascular disease states and can be induced in non-endothelial cells during the progression of cardiovascular disease. The importance of ACE in the regulation of vascular function and homeostasis is best illustrated by the protective effects of ACE inhibitors against the progression of cardiovascular disease observed in human subjects as well as in various animal models. Some of the apparently beneficial effects of ACE inhibitors however cannot be attributed to the inhibition of angiotensin II generation or the prevention of bradykinin degradation. Over the last two years we have collected intriguing new evidence to indicate that ACE is a signal transduction molecule, which is involved in outside-in signalling in as much as the binding of an ACE substrate or an ACE inhibitor to ACE is able to elicit intracellular events. The aims of this research proposal are to: 1) elucidate the intracellular events affected by ACE signalling as well as the physiological consequences of their activation and 2) clarify the factors and stimuli determining ACE expression in endothelial cells and as a consequence may affect downstream signalling.