AUTHOR=Villalobos Laura A. , San Hipólito-Luengo Álvaro , Ramos-González Mariella , Cercas Elena , Vallejo Susana , Romero Alejandra , Romacho Tania , Carraro Raffaele , Sánchez-Ferrer Carlos F. , Peiró Concepción
TITLE=The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and -Independent Pro-inflammatory Signaling in Human Vascular Smooth Muscle Cells
JOURNAL=Frontiers in Pharmacology
VOLUME=7
YEAR=2016
URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00482
DOI=10.3389/fphar.2016.00482
ISSN=1663-9812
ABSTRACT=Background and Aims: Targeting inflammation is nowadays considered as a challenging pharmacological strategy to prevent or delay the development of vascular diseases. Angiotensin-(1-7) is a member of the renin-angiotensin system (RAS) that binds Mas receptors and has gained growing attention in the last years as a regulator of vascular homeostasis. Here, we explored the capacity of Ang-(1-7) to counteract human aortic smooth muscle cell (HASMC) inflammation triggered by RAS-dependent and -independent stimuli, such as Ang II or interleukin (IL)-1β.
Methods and Results: In cultured HASMC, the expression of inducible nitric oxide synthase (iNOS) and the release of nitric oxide were stimulated by both Ang II and IL-1β, as determined by Western blot and indirect immunofluorescence or the Griess method, respectively. iNOS induction was inhibited by Ang-(1-7) in a concentration-dependent manner. This effect was equally blocked by two different Mas receptor antagonists, A779 and D-Pro7-Ang-(1-7), suggesting the participation of a unique Mas receptor subtype. Using pharmacological inhibitors, the induction of iNOS was proven to rely on the consecutive upstream activation of NADPH oxidase and nuclear factor (NF)-κB. Indeed, Ang-(1-7) markedly inhibited the activation of the NADPH oxidase and subsequently of NF-κB, as determined by lucigenin-derived chemiluminescence and electromobility shift assay, respectively.
Conclusion: Ang-(1-7) can act as a counter-regulator of the inflammation of vascular smooth muscle cells triggered by Ang II, but also by other stimuli beyond the RAS. Activating or mimicking the Ang-(1-7)/Mas axis may represent a pharmacological opportunity to attenuate the pro-inflammatory environment that promotes and sustains the development of vascular diseases.