title: The Angiotensin-(1-7)/Mas Axis Counteracts Angiotensin II-Dependent and -Independent Pro-inflammatory Signaling in Human Vascular Smooth Muscle Cells.
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.
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Villalobos
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: San Hipólito-Luengo
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Mariella
authors.initials: M
authors.lastname: Ramos-González
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Cercas
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Vallejo
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Romero
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Romacho
authors.affiliation: Service of Endocrinology, Hospital de La PrincesaMadrid, Spain; Department of Medicine, School of Medicine, Universidad Autónoma de MadridMadrid, Spain.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Carraro
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Sánchez-Ferrer
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Peiró
keywords: Mas receptors; angiotensin-(1-7); cell signaling; cytokines; inducible nitric oxide synthase; inflammation; interleukin-1β; vascular smooth muscle