Bioactive angiotensin peptides: focus on angiotensin IV

Abstract

The ability of Ang II (1-7) to mediate and oppose Ang II actions has been recently reviewed. [46][47][48][49] Angiotensin 1-9 and ACE2 Recently, a novel ACE-related enzyme (ACE2) has also been discovered, that catalyses carboxypeptidase cleavage of Ang I to generate Ang (1-9), which subsequently serves as a substrate for the generation of Ang II (1-7). ACE2 is found on the endothelium of coronary and intrarenal vessels and renal tubular epithelium, raising the possibility that the formation of Ang II (1-7) may be important in regulating cardiac and renal function. 50,51 Angiotensin IV Angiotensin IV (Ang IV), originally considered to be biologically inactive, has attracted recent attention because of its ability to elicit many biological actions. Ang IV binds with high affinity to a pharmacologically-distinct binding site, designated the AT 4 receptor. 52,53 This binding site shows highest selectivity for Ang IV, with approximately 10-fold lower affinity for Ang III. Affinities for Ang II and [Sar 1 -Ile 8 ] Ang II are markedly lower, while losartan, PD 123177 and CGP 42112A show no activity. [54][55][56][57][58] The AT 4 -receptor has a distinct distribution pattern in the brain, being found in regions associated with cognitive, sensory and motor function in the guinea pig, 55 sheep 59 and monkey. 60 We recently localised the AT 4 receptor in human forebrain, midbrain, and pons, using an iodinated Ang IV analogue, Norleucine 1 -Ang IV (Nle 1 -Ang IV), a more stable analogue of Ang IV with higher affinity for the AT 4receptor. The distribution of the AT 4 -receptor in the human brain was similar to that reported in other species. 61 The AT 4 -receptor is also found in abundance in peripheral tissues, such as the heart, adrenal cortex, kidney, vascular smooth muscle cells and numerous other tissues. 62 REVIEW Figure 1 Schematic representation of the enzymatic events leading to the formation of angiotensin peptides.

Evaluation of Metabolically Stabilized Angiotensin IV Analogs as Procognitive/Antidementia Agents

“…These observations have long encouraged the notion that AngIV-based pharmaceuticals may have potential as antidementia therapeutics (Mustafa et al, 2001;von Bohlen und Halbach, 2003;Gard, 2004Gard, , 2008De Bundel et al, 2008;Wright and Harding, 2010). The transformation of AngIV and earlier described analogs into clinically useful agents has been impeded by their lack of metabolic stability and inability to penetrate the blood-brain barrier (BBB).…”

A comparison of the effects of Angiotensin IV on androgen-dependent and androgen-independent prostate cancer cell lines

“…However, IRAP is associated with stimulation rather than inhibition of cell proliferation. 12,13 Another mechanism by which Ang IV might exert its cell biological role is based on its partial homology with a region on the hepatocyte growth factor (HGF/c-Met signalling). Highly invasive prostate cancer cells express c-Met at levels well above those observed in less aggressive cancers.…”

“…For instance, Ang IV regulates not only blood flow and memory retention but also inflammation, cell proliferation and differentiation. [10][11][12][13] Ang IV can mediate biological effects by interaction with the classic receptors AT1 and AT2, which belong to the G protein-coupled receptor family (GPCR), and through binding to the receptor AT4, which has been identified as the enzyme insulin regulated aminopeptidase (IRAP). It is known that Ang IV appears to affect the modulation of certain mitogen-activated protein kinases (MAPKs), protein tyrosine kinases (PTKs) and NF-β signal activation.…”

“…However, the mechanism of action of Ang IV and its physiological significance is still debated. [11][12][13] The aims of this study were to evaluate the effects of Ang IV on cell viability and proliferation in androgendependent and androgen-independent prostate cancer cell lines, as well as to determine the effects of Ang IV on classic angiotensin receptors.…”

Blood pressure and renal hemodynamic effects of angiotensin fragments

“…These metabolites have long been considered of little importance, but are now known to exert biological activity. [4][5][6] This is also the case for other Ang fragments: the heptapeptide Ang-(1-7), which is processed from Ang I by tissue endopeptidases, 7 and the octapeptide Ang A, which is generated from Ang II by enzymatic decarboxylation of Asp. 1, 8 The RAS was originally regarded as a circulating system; however, the existence of 'local' or 'tissue' RAS has been identified in most organs.…”