Characterization of Salt III as new possible allosteric modulator of Angiotensin I Converting Enzyme

Abstract

Angiotensin I Converting Enzyme (ACE) is a glycoprotein that plays an important function in vascular and electrolyte homeostasis. Recently signaling pathways triggered by ACE was described in endothelial cells, showing that it could be a signaling transducer molecule. Several data demonstrated that inhibitors and substrates of ACE and its product Angiotensin II (AII), evoke intracellular signaling pathways activation. During the study of new AT1 receptor antagonists on blood pressure (BP), our group detected that Salt III had no classical effect in reducing BP in spontaneous hypertensive rats, but increased their BP (6 mmHg) at 15 minutes, suggesting a modulation of ACE activity. Incubating Salt III plus Angiotensin I [AI], and plasma ACE, happened a faster conversion of AI into AII when compared to control (AI plus plasma ACE), in the first 10 minutes of reaction. Pesquero group described that ACE could act as an AII receptor-like. Salt III was able to increase the binding sites of AII with ACE transfected in CHO cells. At the moment we are analyzing JNK and ERK1/2 signaling pathways triggered by ACE activation as result of interaction with Salt III. Salt III that act as an activator of AII binding ACE, and is able to modulate signaling pathways iniciated by ACE could clearly emerge as possible tool for treatment of many disorders such as in diabetes and various renal diseases.