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.