Introduction

Johnston, Colin I.

doi:10.1159/000186026

Cited by 4 publications

(2 citation statements)

References 12 publications

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“…In the RAS system, the first enzyme involved is the acid aspartate-protease renin [ 11 ], which converts angiotensinogen to angiotensin I (AngI). This angiotensin is inactive, and is converted to active angiotensin II (AngII) by the dipeptidilcarboxypeptidase angiotensin-converting enzyme (ACE-1) [ 12 ]. Through a similar mechanism of AngII metabolism are produced active angiotensin III (AngIII) and angiotensin IV (AngIV), with the involvement of angiotensinases of aminopeptidase-type.…”

Section: Introductionmentioning

confidence: 99%

“…AngII and AngIII mediates their action through AT 1 and AT 2 receptor subtypes [ 14 , 15 ], whereas AngIV seems to act at the AT 4 receptor subtype [ 4 ], which has been identified as the enzyme insulin-regulated aminopeptidase (IRAP) or, more recently, as the hepatocyte growth factor (HGF)/c-Met receptor system [ 5 ]. On the other hand, tissue carboxypeptidases and other proteolytic enzymes (such as trypsin, chymotrypsin, pepsin and others) contribute to the inactivation of the active forms of angiotensins, transforming them into inactive fragments and amino acid constituents [ 4 , 12 ]. A separate pathway for the synthesis of AngIII, independent of AngII formation, is via the nonapeptide [des-Asp1]AngI, formed from AngI by ASAP [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Anti-Inflammatory and Antitumor Effects of Hydroxytyrosol but Not Oleuropein on Experimental Glioma In Vivo. A Putative Role for the Renin-Angiotensin System

Ramírez-Expósito

Martínez-Martos

2018

Biomedicines

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Functional roles of the angiotensin peptides of the renin-angiotensin system (RAS) cascade can be analyzed through their corresponding proteolytic regulatory enzymes aspartyl aminopeptidase (ASAP), aminopeptidase A (APA), aminopeptidase B (APB), aminopeptidase N (APN) and insulin-regulated aminopeptidase (IRAP). These enzyme activities generate active or inactive angiotensin peptides that alter the ratios between their bioactive forms, regulating several important processes such as the regulation of cardiovascular functions, body water regulation, normal memory consolidation and retrieval, but also cell growth, differentiation and apoptosis or the inflammatory response. We have previously described that the treatment with hydroxytyrosol but not with oleuropein or with the mixture of both compounds led to the significant inhibition of tumor growth in an in vivo glioma model by mechanisms not only related to redox balance. Using this glioma model, here we analyze the effects of the phenolic compounds oleuropein and hydroxytyrosol in circulating RAS-regulating ASAP, APA, APN, APB and IRAP specific activities and the pro-inflammatory cytokines IL-6 and TNFα to understand the relationship between the antitumor and anti-inflammatory effects of hydroxytyrosol, but not oleuropein, and the components of the RAS. We found that oleuropein increased all the activities analyzed and promoted a pro-inflammatory status, whereas hydroxytyrosol only modified ASAP and IRAP activities and promotes an anti-inflammatory status. When administrated together, oleuropein overrode the effects of hydroxytyrosol. Our results suggest a role for angiotensin III and angiotensin 1-7 in both tumor growth inhibition and anti-inflammatory response promoted by hydroxytyrosol.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory and Antitumor Effects of Hydroxytyrosol but Not Oleuropein on Experimental Glioma In Vivo. A Putative Role for the Renin-Angiotensin System

Ramírez-Expósito

Martínez-Martos

2018

Biomedicines

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Ang II and Ang IV: Unraveling the Mechanism of Action on Synaptic Plasticity, Memory, and Epilepsy

Bundel¹,

Smolders²,

Vanderheyden³

et al. 2008

CNS Neuroscience & Therapeutics

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The central angiotensin system plays a crucial role in cardiovascular regulation. More recently, angiotensin peptides have been implicated in stress, anxiety, depression, cognition, and epilepsy. Angiotensin II (Ang II) exerts its actions through AT(1) and AT(2) receptors, while most actions of its metabolite Ang IV were believed to be independent of AT(1) or AT(2) receptor activation. A specific binding site with high affinity for Ang IV was discovered and denominated "AT(4) receptor". The beneficiary effects of AT(4) ligands in animal models for cognitive impairment and epileptic seizures initiated the search for their mechanism of action. This proved to be a challenging task, and after 20 years of research, the nature of the "AT(4) receptor" remains controversial. Insulin-regulated aminopeptidase (IRAP) was first identified as the high-affinity binding site for AT(4) ligands. Recently, the hepatocyte growth factor receptor c-MET was also proposed as a receptor for AT(4) ligands. The present review focuses on the effects of Ang II and Ang IV on synaptic transmission and plasticity, learning, memory, and epileptic seizure activity. Possible interactions of Ang IV with the classical AT(1) and AT(2) receptor subtypes are evaluated, and other potential mechanisms by which AT(4) ligands may exert their effects are discussed. Identification of these mechanisms may provide a valuable target in the development in novel drugs for the treatment of cognitive disorders and epilepsy.

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Circulating Aminopeptidase Activities in Men and Women with Essential Hypertension

Ortega

Saavedra-Alías²,

Liébana-Cañada³

et al. 2013

CMC

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Essential hypertension is one of the major contributors to premature morbidity and mortality due to the incresased risk for coronary heart disease, stroke, renal disease, peripheral vascular disease and vascular dementia for both men and women. However, its basic causes remain unknown. In the present work we studied the activity of several proteolytic regulatory enzymes related to renin-angiotensin-system (RAS) (aminopeptidase A, APA; aminopeptidase N, APN; aminopeptidase B, APB; and insulin-regulated aminopeptidase, IRAP); with oxytocin regulation (oxytocinase); with the metabolism of GnRH and TRH (pyrrolidone carboxypeptidase, Pcp); and with enkephalins metabolism (enkephalindegrading activity, EDA), to elucidate their role in the mechanisms responsible of essential hypertension and to discuss the possible gender differences. Serum samples of 53 individuals with essential hypertension and 60 healthy volunteers were collected and used to assay enzyme activities, gonad hormones testosterone and estradiol, TSH and free thyroxin (fT4). Differences were observed in APA, APN, Pcp and EDA specific activities, and in serum gonad hormone levels between hypertensive and control groups. Only Pcp activity showed gender differences. Regarding the RAS, APA is reduced while APN is increased, suggesting increased levels of angiotensin II and a facilitation of the conversion of angiotensin III in angiotensin IV. Thus, the changes in several RAS-regulating specific activities and other enzyme activities involved in the neuroendocrine modulation of gonad and stress-related functions are related to essential hypertension with minor gender differences. Therefore, aminopeptidases constitute new elements for the knowledge of the causes of essential hypertension and an alternative as therapeutic targets against the illness.

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Introduction

Cited by 4 publications

References 12 publications

Anti-Inflammatory and Antitumor Effects of Hydroxytyrosol but Not Oleuropein on Experimental Glioma In Vivo. A Putative Role for the Renin-Angiotensin System

Anti-Inflammatory and Antitumor Effects of Hydroxytyrosol but Not Oleuropein on Experimental Glioma In Vivo. A Putative Role for the Renin-Angiotensin System

Ang II and Ang IV: Unraveling the Mechanism of Action on Synaptic Plasticity, Memory, and Epilepsy

Circulating Aminopeptidase Activities in Men and Women with Essential Hypertension

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