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

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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.