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.
Highlights
Vascular inflammation is a key feature of vascular diseases, like hypertension or atherosclerosis, which are major causes of mortality worldwide (Daiber et al, 2016)
We evaluated the capacity of Ang-(1-7) to counteract the pro-inflammatory response triggered by Ang II in primary human vascular smooth muscle cells (VSMC) cultures in terms of nuclear factor (NF)-κB activation and inducible nitric oxide synthase induction
While Ang-(1-7) has been gradually acknowledged as a physiological antagonist of Ang II, very little is known about the capacity of Ang-(1-7) to modulate the pro-inflammatory responses elicited by renin-angiotensin system (RAS)-independent agonists
Summary
Vascular inflammation is a key feature of vascular diseases, like hypertension or atherosclerosis, which are major causes of mortality worldwide (Daiber et al, 2016). Activated VSMC can switch to a pro-inflammatory phenotype that drives the expression of a wide array of pro-inflammatory molecules and mediators, which in turn perpetuate and amplify the deleterious vascular environment (Lacolley et al, 2012; Chistiakov et al, 2015). In this context, attenuating inflammation, by pharmacological tools or other approaches, is nowadays considered as a challenging strategy to prevent or delay the development of vascular diseases (Everett et al, 2013; Daiber et al, 2016). 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
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