AVE 0991, a non‐peptide mimic of angiotensin‐(1–7) effects, attenuates pulmonary remodelling in a model of chronic asthma

Abstract

BACKGROUND AND PURPOSEAVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation. EXPERIMENTAL APPROACHWe used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 μg·mouse −1 , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg −1 ·per day, s.c.) or saline (100 μL·kg −1 ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates. KEY RESULTSTreatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs. CONCLUSIONS AND IMPLICATIONSAVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.

Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model

“…Most reports showed that the airway responsiveness to methacholine, a muscarinic agonist analogous to carbachol, increased in asthmatic rats (Cho et al, 2004;Deng et al, 2013) whereas in our study, asthmatic rats showed a drastic fall in the airway responsiveness to carbachol similar to that reported by Rodrigues-Machado et al (Rodrigues-Machado et al, 2013), who provided a plausible explanation. Attenuated tracheal ring contractions suggest that the airways in these rats underwent an extensive remodelling, that prevented the contraction in response to muscarinic receptor stimulation.…”

“…So we generated cumulative concentration-response curves with carbachol (10 -10 to 10 -5 M), which is a muscarinic receptor agonist to get an insight about function and structural alterations of airways (Rodrigues-Machado et al, 2013). There was a significant attenuation of contraction in asthma rats (Fig.…”

Heat Shock Prevents Insulin Resistance–Induced Vascular Complications by Augmenting Angiotensin-(1-7) Signaling

“…Recently, the therapeutic potential of ANG-(1-7) axis was highlighted by the development of an orally active nonpeptide Mas agonist, such as AVE 0991 and CGEN-865S. AVE 0991 showed beneficial effects in heart dysfunction, atherosclerosis, blood pressure, and pulmonary remodeling (53)(54)(55)(56). These observations further confirm the protective role of ANG-(1-7) in different models of cardiovascular disorders.…”

Vascular function in asthmatic children and adolescents

“…Recently we demonstrated [38, 39] in a model of chronic asthma induced by ovalbumin (OVA) that asthmatic mice exhibited an increase in size and number of vessels within the airway wall, contributing to thickening of the wall. OVA mice also presented a significant increase in myocyte diameter of the right ventricle, suggesting that structural remodeling led to an increase in pulmonary vascular resistance and subsequent right ventricular hypertrophy.…”