Anti-inflammatory effects of angiotensin-(1-7) in ischemic stroke

Abstract

Previously we demonstrated that central administration of angiotensin-(1-7) [Ang-(1-7)] into rats elicits significant cerebroprotection against ischemic stroke elicited by endothelin-1 induced middle cerebral artery occlusion. Ang-(1-7), acting via its receptor Mas, reduced cerebral infarct size, and rats exhibited improved performance on neurological exams. These beneficial actions of Ang-(1-7) were not due to inhibition of the effects of endothelin-1 on cerebral vasoconstriction or effects on cerebral blood flow, and so we considered other potential mechanisms. Here we investigated the possibility that the Ang-(1-7)-induced cerebroprotection involves an anti-inflammatory effect, since stroke-induced cerebral damage includes an excessive intracerebral inflammatory response. Our quantitative RT-PCR analyses revealed that central Ang-(1-7) treatment attenuates the increased expression of mRNAs for inducible nitric oxide synthase (iNOS), several pro-inflammatory cytokines and cluster of differentiation molecule 11b (microglial marker) within the cerebral cortex following endothelin-1 induced stroke. Western blotting confirmed similar changes in iNOS protein expression in the cerebral cortex. In support of these observations, immunostaining revealed the presence of immunoreactive Mas on activated microglia within the cerebral cortical infarct zone, and in vitro experiments demonstrated that lipopolysaccharide-induced increases in nitric oxide production in glial cultures are attenuated by Ang-(1-7) acting via Mas. Collectively these findings demonstrate an anti-inflammatory action of Ang-(1-7) in the brain, and suggest that the cerebroprotective action of this peptide in ischemic stroke may involve effects on nitric oxide generation by microglia.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Reduction in baroreflex sensitivity and sympathetic activity is observed in Mas-null mice (Walther et al, 2000b). In addition Ang(1-7) and MAS provide a protective effect in models of stroke (Mecca et al, 2011;Regenhardt et al, 2013Regenhardt et al, , 2014a. MAS is present in select regions of the brain, which provides the structural basis for many effects produced by Ang (1)(2)(3)(4)(5)(6)(7) in the brain.…”

Intracerebroventricular Infusion of Angiotensin-(1–7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease

“…A growing body of evidence indicates that angiotensin-(1-7) and its receptor, the Mas receptor, are widely distributed in the central nervous system [20] and are potentially involved in the pathophysiology of brain diseases [9,[21][22]. However, to our knowledge, there is no report investigating the potential role of angiotensin-(1-7)/Mas receptor axis in AD.…”

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…The absence of the antidiuretic action of Ang-(1-7) in Mas-KO mice is in agreement with the antidiuretic effect of Ang-(1-7) in water-loaded rats (Santos and Baracho, 1992). Diverging from many reports describing Mas-mediated anti-inflammatory effects in different tissues (Al-Maghrebi et al, 2009;da Silveira et al, 2010;El-Hashim et al, 2012;Giani et al, 2012;Jiang et al, 2012;Santos et al, 2012;Souza and Costa-Neto, 2012;Sukumaran et al, 2012;Chen et al, 2013;Feltenberger et al, 2013;Moore et al, 2013;Regenhardt et al, 2013;Wagenaar et al, 2013;Wang et al, 2013c;Acuna et al, 2014;Meng et al, 2014), in the kidney, a proinflammatory role for Ang-(1-7) and Mas was reported by using a model of unilateral ureteral obstruction in mice (Esteban et al, 2009). In contrast, anti-inflammatory and beneficial effects of Ang-(1-7) were observed in other models of kidney injury (Singh et al, 2010b;Moon et al, 2011;Bernardi et al, 2012;Giani et al, 2012;Harris, 2012;Chou et al, 2013;Santos et al, 2013b;Zhang et al, 2014).…”