<scp>A</scp>ngiotensin‐(1‐7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation

Magalhães, Giselle Santos; Rodrigues-Machado, Maria Glória; Motta‐Santos, Daisy; Silva, A R; Caliari, Marcelo Vidigal; Prata, Luana Oliveira; Abreu, Soraia C.; Rocco, Patricia R. M.; Barcelos, Lucíola da Silva; Santos, Robson Augusto Souza; Campagnole‐Santos, Maria José

doi:10.1111/bph.13057

Cited by 87 publications

(114 citation statements)

References 61 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Vascular function in asthmatic children and adolescents

et al. 2017

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BackgroundEpidemiological studies have demonstrated an increased incidence of cardiovascular events in patients with bronchial asthma, but little is known about the relationship between asthma and vascular function. The purpose of this study was to evaluate endothelial function and arterial stiffness in children and adolescents with asthma.MethodsA cross-sectional controlled study was designed. Measurements of endothelial function and arterial stiffness in asthmatic (13.6 ± 0.6 years) and control groups (14.9 ± 0.7 years) were taken by the non-invasive peripheral arterial tonometry (EndoPAT2000) determined by using the natural logarithm of the reactive hyperemia index (LnRHI) and the augmentation index (AIx@75%), respectively. Patients with asthma were also administered two questionnaires to evaluate asthma control and quality of life. Exercise functional capacity was evaluated using the Shuttle Walking Test (SWT). Only male participants were included in the present study.ResultsLnRHI and the walked distance during the SWT were similar between groups (p = 0.23 and p = 0.50, respectively). AIx@75% was significantly higher in the asthmatic group (-7.75 ± 1.7) compared to the control group (-15.25 ± 1.8), p < 0.04. In the control group, the LnRHI correlated positively with baseline systolic blood pressure (r = 0.53, p = 0.02) and mean arterial pressure (r = 0.50, p = 0.03), age (r = 0.61, p = 0.007), weight (r = 0.63, p = 0.004) and height (r = 0.56, p = 0.015). Besides that LnRHI correlated with FVC (r = 0.69, p = 0.002), FEV1, (r = 0.53, p = 0.03) and negatively with Tiffeneau index (FEV1/FVC%, r = −0.49 p = 0.04). The LnRHI of the asthmatic group did not correlate with the different variables evaluated.ConclusionThe increased AIx@75% without changes in LnRHI in asthmatic patients could mean that an early detection of vascular impairment may precede endothelial dysfunction, and that different mechanisms may contribute to the pathogenesis and progression of cardiovascular events in this population. A large prospective and randomized controlled study should be done to evaluate the physiopathological mechanisms underlying the association between arterial stiffness and asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0488-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Vascular function in asthmatic children and adolescents

et al. 2017

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“…In line with this view, ambrisentan, which was presumably taken up in a more continuous fashion with the drinking water, showed clear beneficial effects in our MCT model. Recently, studies by Magalhães and colleagues 31 in which Ang-(1-7)…”

Section: Discussionmentioning

confidence: 99%

Dose‐Dependent, Therapeutic Potential of Angiotensin‐(1–7) for the Treatment of Pulmonary Arterial Hypertension

et al. 2015

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The effects of the heptapeptide angiotensin-(1-7) (Ang-(1-7)), via its receptor Mas, oppose many of the effects of the classic angiotensin II signaling pathway, and pharmacological exploitation of this effect is currently actively pursued for a wide range of cardiovascular, neoplastic, or immunological disorders. On the basis of its vasodilatory and antiproliferative properties, Ang-(1-7) has consequentially also been proposed as a novel therapeutic strategy for the treatment of pulmonary arterial hypertension (PAH). In this study, we tested the effectiveness of Ang-(1-7) and its stable, cyclic analog cAng-(1-7) over a range of doses for their therapeutic potential in experimental PAH. In the monocrotaline (MCT) rat model of PAH, Ang-(1-7) or cAng-(1-7) were injected in doses of 30, 100, 300, or 900 μg kg, and effects on pulmonary hemodynamics and vascular remodeling were assessed. Five weeks after MCT injection, right ventricular systolic pressure (RVSP) was significantly reduced for 3 dose groups treated with Ang-(1-7) (100, 300, and 900 μg kg) and for all dose groups treated with cAng-(1-7), as compared to untreated controls, yet the total reduction of RVSP was <50% at best and thus markedly lower than that with a positive treatment control with ambrisentan. Medial-wall thickness in pulmonary arterioles was only slightly reduced, without reaching significance, for any of the tested Ang-(1-7) compounds and doses. The reported moderate attenuation of PAH does not confirm the previously postulated high promise of this strategy, and the therapeutic usefulness of Ang-(1-7) may be limited in PAH relative to that in other cardiovascular diseases.Keywords: pulmonary hypertension, vascular remodeling, renin-angiotensin system. Pulmonary arterial hypertension (PAH) is a rare but ultimately fatal disease defined by an increase in mean pulmonary arterial pressure to >25 mmHg at rest or >30 mmHg during exercise.1 The pathogenesis of PAH is very diverse, in that PAH may be heritable or idiopathic or develop in association with a number of diseases, such as systemic sclerosis or HIV infection. The pathology of PAH is characterized by endothelial dysfunction, which becomes apparent as an imbalance in the release of vasoconstrictive and vasodilatory factors, such as endothelin and nitric oxide (NO), leading to pulmonary vasoconstriction and ultimately promoting structural remodeling of the pulmonary vasculature, resulting in a persistent elevation in pulmonary vascular resistance. 2,3 A series of therapeutic drugs have been approved for the treatment of PAH that target three different pathways: prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. 4 While these drugs have helped to improve life expectancy and quality of life in PAH patients in the past 2 decades, mortality remains high, as one-third of PAH patients die within 3 years of diagnosis; this emphasizes the need for further research and improved therapeutic options.

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“…We also tested the possibility that pharmacological inhibition of such early inflammation would translate into protection from atherosclerosis and into increased plaque stability. We focused on a strategy concomitantly known to modulate inflammation and vascular responses, such as activation of angiotensin 1–7 (Ang‐(1–7)) receptors, as this could provide a viable alternative for anti‐inflammatory interventions in atherosclerosis, as well as other vascular diseases, without concerns associated with significant systemic immunosuppression (Passos‐Silva et al, ; Magalhaes et al, ).…”

Section: Introductionmentioning

confidence: 99%

Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

Skiba

Nosalski

Mikołajczyk

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEInflammation plays a key role in atherosclerosis. The protective role of angiotensin 1-7 (Ang-(1-7)) in vascular pathologies suggested the therapeutic use of low MW, non-peptide Ang-(1-7) mimetics, such as AVE0991. The mechanisms underlying the vasoprotective effects of AVE0991, a Mas receptor agonist, remain to be explored. EXPERIMENTAL APPROACHWe investigated the effects of AVE0991 on the spontaneous atherosclerosis in apolipoprotein E (ApoE)À/À mice, in the context of vascular inflammation and plaque stability. KEY RESULTSAVE0991 has significant anti-atherosclerotic properties in ApoEÀ/À mice and increases plaque stability, by reducing plaque macrophage content, without effects on collagen. Using the descending aorta of chow-fed ApoEÀ/À mice, before significant atherosclerotic plaque develops, we gained insight to early events in atherosclerosis. Interestingly, perivascular adipose tissue (PVAT) and adventitial infiltration with macrophages and T-cells precedes atherosclerotic plaque or the impairment of endothelium-dependent NO bioavailability (a measure of endothelial function). AVE0991 inhibited perivascular inflammation, by reducing chemokine expression in PVAT and through direct actions on monocytes/macrophages inhibiting their activation, characterized by production of IL-1β, TNF-α, CCL2 and CXCL10, and differentiation to M1 phenotype. Pretreatment with AVE0991 inhibited migration of THP-1 monocytes towards supernatants of activated adipocytes (SW872). Mas receptors were expressed in PVAT and in THP-1 cells in vitro, and the anti-inflammatory effects of AVE0991 were partly Mas dependent. CONCLUSIONS AND IMPLICATIONSThe selective Mas receptor agonist AVE0991 exhibited anti-atherosclerotic and anti-inflammatory actions, affecting monocyte/macrophage differentiation and recruitment to the perivascular space during early stages of atherosclerosis in ApoEÀ/À mice.

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Angiotensin‐(1‐7) attenuates airway remodelling and hyperresponsiveness in a model of chronic allergic lung inflammation

Cited by 87 publications

References 61 publications

Vascular function in asthmatic children and adolescents

Vascular function in asthmatic children and adolescents

Dose‐Dependent, Therapeutic Potential of Angiotensin‐(1–7) for the Treatment of Pulmonary Arterial Hypertension

Anti‐atherosclerotic effect of the angiotensin 1–7 mimetic AVE0991 is mediated by inhibition of perivascular and plaque inflammation in early atherosclerosis

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