BackgroundThe angiotensin-I converting enzyme (ACE) plays a central role in the renin-angiotensin system, acting by converting the hormone angiotensin-I to the active peptide angiotensin-II (Ang-II). More recently, ACE was shown to act as a receptor for Ang-II, and its expression level was demonstrated to be higher in melanoma cells compared to their normal counterparts. However, the function that ACE plays as an Ang-II receptor in melanoma cells has not been defined yet.AimTherefore, our aim was to examine the role of ACE in tumor cell proliferation and migration.ResultsWe found that upon binding to ACE, Ang-II internalizes with a faster onset compared to the binding of Ang-II to its classical AT1 receptor. We also found that the complex Ang-II/ACE translocates to the nucleus, through a clathrin-mediated process, triggering a transient nuclear Ca2+ signal. In silico studies revealed a possible interaction site between ACE and phospholipase C (PLC), and experimental results in CHO cells, demonstrated that the β3 isoform of PLC is the one involved in the Ca2+ signals induced by Ang-II/ACE interaction. Further studies in melanoma cells (TM-5) showed that Ang-II induced cell proliferation through ACE activation, an event that could be inhibited either by ACE inhibitor (Lisinopril) or by the silencing of ACE. In addition, we found that stimulation of ACE by Ang-II caused the melanoma cells to migrate, at least in part due to decreased vinculin expression, a focal adhesion structural protein.ConclusionACE activation regulates melanoma cell proliferation and migration.
Abstract-Angiotensin-converting enzyme (ACE) is an ectoprotein able to modulate the activity of a plethora of compounds, among them angiotensin I and bradykinin. Despite several decades of research, new aspects of the mechanism of action of ACE have been elucidated, expanding our understanding of its role not only in cardiovascular regulation but also in different areas. Recent findings have ascribed an important role for ACE/kinin B 2 receptor heterodimerization in the pharmacological properties of the receptor. In this work, we tested the hypothesis that this interaction also affects ACE enzymatic activity. ACE catalytic activity was analyzed in Chinese hamster ovary cell monolayers coexpressing the somatic form of the enzyme and the receptor coding region using as substrate the fluorescence resonance energy transfer peptide Abz-FRK(Dnp)P-OH. Results show that the coexpression of the kinin B 2 receptor leads to an augmentation in ACE activity. In addition, this effect could be blocked by the B 2 receptor antagonist icatibant. The hypothesis was also tested in endothelial cells, a more physiological system, where both proteins are naturally expressed. Endothelial cells from genetically ablated kinin B 2 receptor mice showed a decreased ACE activity when compared with wild-type mice cells. In summary, this is the first report showing that the ACE/kinin B 2 receptor interaction modulates ACE activity. Taking into account the interplay among ACE, ACE inhibitors, and kinin receptors, we believe that these results will shed new light into the arena of the controversial search for the mechanism controlling these interactions. Key Words: ACE Ⅲ kinin B 2 receptor Ⅲ dimerization Ⅲ enzyme activity Ⅲ ACE inhibitors Ⅲ icatibant A ngiotensin-converting enzyme (ACE) is a transmembrane zinc metallopeptidase that cleaves carboxyterminal dipeptides from several substrates and is abundant in vascular endothelial cells. 1,2 An ACE soluble form found in plasma is derived from the membrane-bound form by shedding. 3,4 ACE plays a major role in regulating cardiovascular functions, because it converts the decapeptide angiotensin (Ang) I into the vasoconstrictor and proliferative octapeptide Ang II and inactivates the vasodilatory nonapeptide bradykinin (BK). 5 The enzyme also hydrolyzes other substrates like angiotensin 1-7, Ac-SDKP, substance P, cholecystokinin, hemopressin, and amyloid -protein (reviewed by Reference 6). ACE inhibition is a valuable therapy for the management of hypertension and cardiac failure. Several data support the proposal that many effects of ACE inhibitors are because of the inhibition of Ang II generation. 7 However, accumulating evidence indicates that several antihypertensive and cardioprotective effects of ACE inhibitors may be because of reduced BK degradation, with resultant increased endogenous BK levels. 8,9 Numerous studies suggest that these compounds not only facilitate the accumulation of locally formed BK but also directly affect kinin B 2 receptor signaling, resulting in an enhanced response t...
We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin–angiotensin and kallikrein–kinin systems.
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