Mas receptor activation facilitates innate hematoma resolution and neurological recovery after hemorrhagic stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating neurological disease causing severe sensorimotor dysfunction and cognitive decline, yet there is no effective treatment strategy to alleviate outcomes of these patients. The Mas axis-mediated neuroprotection is involved in the pathology of various neurological diseases, however, the role of the Mas receptor in the setting of ICH remains to be elucidated. METHODS: C57BL/6 mice were used to establish the ICH model by injection of collagenase into mice striatum. The Mas receptor agonist AVE0991 was administered intranasally (0.9 mg/kg) after ICH. Using a combination of behavioral tests, Western blots, immunofluorescence staining, hematoma volume, brain edema, quantitative-PCR, TUNEL staining, Fluoro-Jade C staining, Nissl staining, and pharmacological methods, we examined the impact of intranasal application of AVE0991 on hematoma absorption and neurological outcomes following ICH and investigated the underlying mechanism. RESULTS: Mas receptor was found to be significantly expressed in activated microglia/macrophages, and the peak expression of Mas receptor in microglia/macrophages was observed at approximately 3-5 days, followed by a subsequent decline. Activation of Mas by AVE0991 post-treatment promoted hematoma absorption, reduced brain edema, and improved both short- and long-term neurological functions in ICH mice. Moreover, AVE0991 treatment effectively attenuated neuronal apoptosis, inhibited neutrophil infiltration, and reduced the release of inflammatory cytokines in perihematomal areas after ICH. Mechanistically, AVE0991 post-treatment significantly promoted the transformation of microglia/macrophages towards an anti-inflammatory, phagocytic, and reparative phenotype, and this functional phenotypic transition of microglia/macrophages by Mas activation was abolished by both Mas inhibitor A779 and Nrf2 inhibitor ML385. Furthermore, hematoma clearance and neuroprotective effects of AVE0991 treatment were reversed after microglia depletion in ICH. CONCLUSIONS: Mas activation can promote hematoma absorption, ameliorate neurological deficits, alleviate neuron apoptosis, reduced neuroinflammation, and regulate the function and phenotype of microglia/macrophages via Akt/Nrf2 signaling pathway after ICH. Thus, intranasal application of Mas agonist ACE0991 may provide promising strategy for clinical treatment of ICH patients.

Encapsulation of troglitazone and AVE0991 by gelation microspheres promotes epithelial transformation of adipose-derived stem cells.

Deformities in human soft tissue caused by trauma or burn present a difficult problem in plastic surgery. In this study, we encapsulated troglitazone and angiotensin 1-7 mimetic AVE0991 in gelation microspheres with the goal of inducing epithelial transformation for potential applications in tissue reconstruction. After troglitazone or AVE0991 were encapsulated to gelation microspheres, their release kinetics and bioactivity were examined. Surface morphology and diameter of the gelation microspheres were evaluated using light microscopy. The release of the drugs was assessed in the presence of human adipose-derived stem cells (ADSCs). Treatment with troglitazone microspheres increased cell viability and activated the ß-catenin in ADSCs. Moreover, the AVE0991 microspheres also increased cell viability and C-myc expression of ADSCs. These results showed that troglitazone and AVE0991 microspheres promoted the activity of ADSCs. Furthermore, ADSCs were co-treated with troglitazone and AVE0991 microspheres. Western blot and immunofluorescent staining showed that co-treatment with troglitazone and AVE0991 microspheres elevated the expression of epithelialization associated protein CK14 in ADSCs. In conclusion, our findings indicate that microspheres with troglitazone and AVE0991 can significantly improve the viability and epithelialization of ADSCs, which provides a new approach for the construction of tissue-engineered skin.

Neuroinflammation in hypertension: the renin-angiotensin system versus pro-resolution pathways.

Overstimulation of the pro-inflammatory pathways within brain areas responsible for sympathetic outflow is well evidenced as a primary contributing factor to the establishment and maintenance of neurogenic hypertension. However, the precise mechanisms and stimuli responsible for promoting a pro-inflammatory state are not fully elucidated. Recent work has unveiled novel compounds derived from omega-3 polyunsaturated fatty acids (ω-3 PUFAs), termed specialized pro-resolving mediators (SPMs), which actively regulate the resolution of inflammation. Failure or dysregulation of the resolution process has been linked to a variety of chronic inflammatory and neurodegenerative diseases. Given the pathologic role of neuroinflammation in the hypertensive state, SPMs and their associated pathways may provide a link between hypertension and the long-standing association of dietary ω-3 PUFAs with cardioprotection. Herein, we review recent progress in understanding the RAS-driven pathophysiology of neurogenic hypertension, particularly in regards to the chronic low-grade neuroinflammatory response. In addition, we examine the potential for an impaired resolution of inflammation process in the context of hypertension.

AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress.

AVE 0991, the nonpeptide angiotensin-(1-7) (Ang-(1-7)) analog, is recognized as having beneficial cardiovascular effects. However, the mechanisms have not been fully elucidated. This study was designed to investigate the effects of AVE 0991 on cardiac hypertrophy and the mechanisms involved. Mice were underwent aortic banding to induce cardiac hypertrophy followed by the administration of AVE 0991 (20 mg kg·day (-1)) for 4 weeks. It was shown that AVE 0991 reduced left ventricular hypertrophy and improved heart function, characterized by decreases in left ventricular weight and left ventricular end-diastolic diameter, and increases in ejection fraction. Moreover, AVE 0991 significantly down-regulated mean myocyte diameter and attenuate the gene expression of the hypertrophic markers. Furthermore, AVE 0991 inhibited the expression of NOX 2 and NOX 4, meaning that AVE 0991 reduced oxidative stress of cardiac hypertrophy mice. Our data showed that AVE 0991 treatment could attenuate cardiac hypertrophy and improve heart function, which may be due to reduce oxidative stress.

Advancement in Beneficial Effects of AVE 0991: A Brief Review.

AVE 0991, a non-peptide analogue of Angiotensin-(1-7) [Ang-(1-7)], is orally active and physiologically well tolerated. Several studies have demonstrated that AVE 0991 improves glucose and lipid metabolism, and contains anti-inflammatory, anti-apoptotic, anti-fibrosis, and anti-oxidant effects. Numerous preclinical studies have also reported that AVE 0991 appears to have beneficial effects on a variety of systemic diseases, including cardiovascular, liver, kidney, cancer, diabetes, and nervous system diseases. This study searched multiple literature databases, including PubMed, Web of Science, EMBASE, Google Scholar, Cochrane Library, and the ClinicalTrials.gov website from the establishment to October 2022, using AVE 0991 as a keyword. This literature search revealed that AVE 0991 could play different roles via various signaling pathways. However, the potential mechanisms of these effects need further elucidation. This review summarizes the benefits of AVE 0991 in several medical problems, including the COVID-19 pandemic. The paper also describes the underlying mechanisms of AVE 0991, giving in-depth insights and perspectives on the pharmaceutical value of AVE 0991 in drug discovery and development.

A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

AVE 0991 Suppresses Astrocyte-Mediated Neuroinflammation of Alzheimer's Disease by Enhancing Autophagy.

Purpose: Our previous study has shown that AVE 0991, a nonpeptide analogue of Ang-(1-7), ameliorates cognitive decline and inhibits NLRP3 inflammasome of astrocytes in Alzheimer's disease model mice. Additionally, several studies have suggested that activation of autophagy appears to effectively inhibit the progression of neuroinflammation. However, it is unclear whether AVE 0991 can modulate astrocyte autophagy to suppress neuroinflammation in Alzheimer's disease. Materials and Methods: APP/PS1 mice and Aß-treated primary astrocytes were used as the research objects in vivo and in vitro, respectively. Water maze test was used to evaluate cognitive function of mice, Nissl staining and immunofluorescence staining was used to assess neuronal damage. ELISA kits were used to detect the levels of Ang-(1-7) and Aß in the cortex, and qRT-PCR was used to detect the expression of cortical inflammation-related mediators. The expression of autophagy-related proteins in cortex were detected by Western blot. The upstream molecular responses involved in inflammation inhibition by AVE 0991 were validated by means of using the Mas1 antagonist and autophagy inhibitor. Results: We found that 30 days of intraperitoneal administration of AVE 0991 improved. Aß deposition, neuronal death, and cognitive deficits in APP/PS1 Alzheimer's disease model mice. Moreover, AVE 0991 treatment greatly suppressed astrocyte-mediated inflammation and up-regulated the expression of autophagy. Furthermore, the inhibitory effect of AVE 0991 on the expression of inflammatory factors was reversed by 3-MA, an autophagy inhibitor. Conclusion: These findings suggest that regulation of autophagy is critical for inhibiting astrocyte neuroinflammatory responses and demonstrate a potential neuroprotective mechanism by which AVE 0991 could suppress neuroinflammatory responses by enhancing autophagy.

Activation of the Mas receptors by AVE0991 and MrgD receptor using alamandine to limit the deleterious effects of Ang II-induced hypertension.

The MrgD receptor agonist, alamandine (ALA) and Mas receptor agonist, AVE0991 have recently been identified as protective components of the renin-angiotensin system. We evaluated the effects of ALA and AVE0991 on cardiovascular function and remodeling in angiotensin (Ang) II-induced hypertension in rats. Sprague Dawley rats were subject to 4-week subcutaneous infusions of Ang II (80 ng/kg/min) or saline after which they were treated with ALA (50 µg/kg), AVE0991 (576 µg/kg), or ALA+AVE0991 during the last 2 weeks. Systolic blood pressure (SBP) and heart rate (HR) values were recorded with tail-cuff plethysmography at 1, 15, and 29 days post-treatment. After euthanization, the heart and thoracic aorta were removed for further analysis and vascular responses. SBP significantly increased in the Ang II group when compared to the control group. Furthermore, Ang II also caused an increase in cardiac and aortic cyclophilin-A (CYP-A), monocyte chemoattractant protein-1 (MCP-1), and cardiomyocyte degeneration but produced a decrease in vascular relaxation. HR, matrix metalloproteinase-2 and -9, NADPH oxidase-4, and lysyl oxidase levels were comparable among groups. ALA, AVE0991, and the drug combination produced antihypertensive effects and alleviated vascular responses. The inflammatory and oxidative stress related to cardiac MCP-1 and CYP-A levels decreased in the Ang II+ALA+AVE0991 group. Vascular but not cardiac angiotensin-converting enzyme-2 levels decreased with Ang II administration but were similar to the Ang II+ALA+AVE0991 group. Our experimental data showed the combination of ALA and AVE0991 was found beneficial in Ang II-induced hypertension in rats by reducing SBP, oxidative stress, inflammation, and improving vascular responses.

Angiotensin-(1-7) Analogue AVE0991 Modulates Astrocyte-Mediated Neuroinflammation via lncRNA SNHG14/miR-223-3p/NLRP3 Pathway and Offers Neuroprotection in a Transgenic Mouse Model of Alzheimer's Disease.

OBJECTIVE: Emerging evidence suggests that brain angiotensin-(1-7) (Ang-(1-7)) deficiency contributes to the pathogenesis of Alzheimer's disease (AD). Meanwhile, our previous studies revealed that restoration of brain Ang-(1-7) levels provided neuroprotection by inhibition of inflammatory responses during AD progress. However, the potential molecular mechanisms by which Ang-(1-7) modulates neuroinflammation remain unclear. MATERIALS AND METHODS: APP/PS1 mice were injected intraperitoneally with AVE0991 (a nonpeptide analogue of Ang-(1-7)) once a day for 30 consecutive days. Cognitive functions, neuronal and synaptic integrity, and inflammation-related markers were assessed. Since astrocytes played a crucial role in AD-related neuroinflammation whilst long noncoding RNAs (lncRNAs) were reported to participate in modulating inflammatory responses, astrocytes of APP/PS1 mice were isolated for high-throughput lncRNA sequencing to identify the most differentially expressed lncRNA following AVE0991 treatment. Afterward, the downstream pathways of this lncRNA in the anti-inflammatory action of AVE0991 were investigated using primary astrocytes. RESULTS: AVE0991 rescued spatial cognitive impairments and alleviated neuronal and synaptic damage in APP/PS1 mice. The levels of Aß1-42 in the brain of APP/PS1 mice were not affected by AVE0991. By employing high-throughput lncRNA sequencing, our in vitro study demonstrated for the first time that AVE0991 suppressed astrocytic NLRP3 inflammasome-mediated neuroinflammation via a lncRNA SNHG14-dependent manner. SNHG14 acted as a sponge of miR-223-3p while NLRP3 represented a direct target of miR-223-3p in astrocytes. In addition, miR-223-3p participated in the AVE0991-induced suppression of astrocytic NLRP3 inflammasome. CONCLUSION: Our results suggest that Ang-(1-7) analogue AVE0991 inhibits astrocyte-mediated neuroinflammation via SNHG14/miR-223-3p/NLRP3 pathway and offers neuroprotection in APP/PS1 mice. These findings reveal the underlying mechanisms by which Ang-(1-7) inhibits neuroinflammation under AD condition and uncover the potential of its nonpeptide analogue AVE0991 in AD treatment.

A Non-Peptidic MAS1 Agonist AVE0991 Alleviates Hippocampal Synaptic Degeneration in Rats with Chronic Cerebral Hypoperfusion.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) is a contributing factor for neurodegenerative diseases. As a recently identified heptapeptide of the brain renin-angiotensin system, angiotensin-(1-7) has been revealed to activate its receptor MAS1 and thus ameliorated cognitive impairments in rats with CCH. Since hippocampal synaptic degeneration represents an important pathological basis of cognitive deficits, we hypothesize that activating MAS1-mediated signaling may alleviate CCH-induced synaptic degeneration in the hippocampus. METHODS: In this study, we tested this hypothesis and uncovered the underlying mechanisms in a rat model of CCH induced by bilateral common carotid artery ligation surgery. At one week after the surgery, rats received a daily intraperitoneal vehicle injection or a non-peptidic MAS1 agonist AVE0991 for 8 weeks. During this procedure, Cerebral Blood Flow (CBF) was recorded. The levels of MAS1, amyloid-ß (Aß), neuroinflammatory cytokines, glial cell markers, and synaptophysin in the hippocampus were assessed at the end of the treatment period. RESULTS: We showed that AVE0991 significantly alleviated hippocampal synaptic degeneration in rats with CCH. This protection might be achieved by facilitating CBF recovery, reducing hippocampal Aß levels, and suppressing neuroinflammatory responses. CONCLUSION: These findings indicate that MAS1-mediated signaling may represent a novel therapeutic target for CCH-related neurodegenerative diseases.

Comparison of the effects of losartan, captopril, angiotensin II type 2 receptor agonist compound 21, and MAS receptor agonist AVE 0991 on myocardial ischemia-reperfusion necrosis in rats.

Myocardial ischemia may occur as a result of pathophysiological and therapeutical applications such as atherosclerosis, thromboembolism, percutaneous transluminal coronary angioplasty, coronary artery bypass, and transplantation. In this study, we aimed to compare the effects of angiotensin (Ang) II type 2 (AT2 ) selective receptor agonist Compound 21 (C21), MAS receptor agonist AVE 0991, Ang II type 1 (AT1 ) selective receptor blocker losartan, and Ang-converting enzyme inhibitor captopril on haemodynamic parameters and infarct size on myocardial ischemia/reperfusion (MI/R)-induced necrosis in rats. To induce necrosis in the heart of rats, reperfusion for 2 h following ischemia for 30 min to the descending branch of the left main coronary artery was achieved. C21 (0.03 mg/kg), AVE 0991 (576 µg/kg), losartan (2 mg/kg), and captopril (3 mg/kg) were administered as an intravenous infusion at 10 min before and throughout the ischemia. Then, the infarct size and risk area were calculated from the heart. The percentage of myocardial infarct size to area at risk ratio (%IS/AR) of groups was Control (MI/R) group: 48.9 ± 8.8%; C21 group: 31.1 ± 7.8%; AVE 0991 group: 29.9 ± 4.8%; C21 + AVE 0991 group: 28.2 ± 3.3%; Losartan + AVE 0991 group: 30.8 ± 5.8%; Captopril + AVE 0991 group: 31.7 ± 7.7%. %IS/AR of the drug-treated groups decreased significantly when compared to the MI/R group (P < 0.05). Our results indicate that the importance of AT1 , AT2 , and MAS receptors in the MI/R injury. Inhibition of Ang II formation by captopril, blockade of AT1 receptor with losartan, and stimulation of AT2 receptor with C21 and MAS receptor with AVE 0991 showed beneficial effects by reducing infarct size.

The Non-peptide Angiotensin-(1-7) Mimic AVE 0991 Attenuates Delayed Neurocognitive Recovery After Laparotomy by Reducing Neuroinflammation and Restoring Blood-Brain Barrier Integrity in Aged Rats.

Delayed neurocognitive recovery (dNCR) after surgery is a common postoperative complication in older adult patients. Our previous studies have demonstrated that cognitive impairment after surgery involves an increase in the brain renin-angiotensin system (RAS) activity, including overactivation of the angiotensin 2/angiotensin receptor-1 (Ang II/AT1) axis, which provokes the disruption of the hippocampal blood-brain barrier (BBB). Nevertheless, the potential role of the counter-regulatory RAS axis, the Ang-(1-7)/Mas pathway, in dNCR remains unknown. Using an aged rat model of dNCR, we dynamically investigated the activity of both axes of the RAS following laparotomy. AVE 0991, a nonpeptide analog of Ang-(1-7), was administered intranasally immediately after laparotomy. We found that the elevation of Ang II, induced by surgery was accompanied by a decrease of Ang-(1-7) in the hippocampus, but not in the circulation. Surgery also significantly downregulated hippocampal Mas receptor expression at 24 h postsurgery. Mas activation with intranasal AVE 0991 treatment significantly improved hippocampus-dependent learning and memory deficits induced by surgery. Furthermore, it attenuated hippocampal neuroinflammation, as shown by the decreased level of the microglial activation marker cluster of differentiation 11b (CD11b) and the decreased production of several inflammatory molecules. Along with these beneficial effects, the AVE 0991 treatment also alleviated the imbalance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), modulated the expression of occludin, and alleviated the IgG extravasation, thereby restoring the integrity of the BBB. In conclusion, these data indicate that activation of Mas by AVE 0991 attenuates dNCR after surgery by reducing neuroinflammation and restoring BBB integrity. Our findings suggest that the Ang-(1-7)/Mas pathway may be a novel therapeutic target for treating dNCR after surgery in older adult patients.

AVE0991, a nonpeptide angiotensin-(1-7) mimic, inhibits angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E knockout mice.

AVE0991, a nonpeptide angiotensin-(1-7) mimic, has similar protective effects for cardiovascular system to Ang-(1-7). In this article, we aimed to explore the effects of AVE0991 and Ang-(1-7) on abdominal aortic aneurysm (AAA) induced by Ang II in apolipoprotein E knockout mice. The mice AAA model was established by Ang II infusion, and then mice received different treatment with saline, Ang II (1.44 mg/kg/day), different dose AVE0991 (0.58 or 1.16 µmol/kg/day), or Ang-(1-7) (400 ng/kg/min). The incidence of AAA was 76%, 48%, 28%, and 24% in the vehicle, the low-dose AVE0991, high-dose AVE0991, and the Ang-(1-7) group, respectively. In comparison with control group, AVE0991 and Ang-(1-7) treatment significantly increased smooth muscle cells and decreased macrophage accumulation, the expression levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor α (TNF-α), and the expression and activity of metalloproteinases 2 and 9 in mice AAA model or in human smooth muscle cells (hVSMCs). The therapeutic effects may be contributed to reduction of oxidative stress and downregulation of P38 and ERK1/2 signal pathways via Mas receptor activation, whereas the positive impacts were reversed by co-administration with the Mas antagonist A779 (400 ng/kg/min) and AVE0991 in Ang II-infused mice or in hVSMCs. Therefore, AVE0991 and Ang-(1-7) might be novel and promising interventions in the prevention and treatment of AAA. KEY MESSAGES: • AVE0991 dose-dependently inhibited Ang II-induced AAA formation in Apoe-/- mice. • Ang-(1-7) played the same protective role as high-dose AVE0991. • Inhibition of Mas receptor with A779 could reverse the protective effect of AVE0991. • The therapeutic effects may be contributed to reduction of oxidative stress and downregulation of P38 and ERK1/2 signal pathways via Mas receptor activation.

AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats.

Oxidative stress and neuronal apoptosis have been demonstrated to be key features in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have indicated that Mas receptor activation initiates an anti-oxidative and anti-apoptotic role in the brain. However, whether Mas activation can attenuate oxidative stress and neuronal apoptosis after SAH remains unknown. To investigate the beneficial effect of Mas on oxidative stress injury and neuronal apoptosis induced by SAH, a total of 196 rats were subjected to an endovascular perforation model of SAH. AVE 0991 (AVE), a selective agonist of Mas, was administered intranasally 1 h after SAH induction. A779, a selective inhibitor of Mas, and small interfering ribonucleic acid (siRNA) for UCP-2 were administered by intracerebroventricular (i.c.v) injection at 1 h and 48 h before SAH induction respectively. Neurological tests, immunofluorescence, TUNEL, Fluoro-Jade C, DHE staining, and Western blot experiments were performed. We found that Mas activation with AVE significantly improved neurobehavioral scores and reduced oxidative stress and neuronal apoptosis in SAH+AVE group compared with SAH+vehicle group. Moreover, AVE treatment significantly promoted phosphorylation of CREB and the expression UCP-2, as well as upregulated expression of Bcl-2 and downregulation of Romo-1 and Bax. The protective effects of AVE were reversed by i.c.v injection of A779 and UCP-2 siRNA in SAH+AVE+A779 and SAH+AVE+UCP-2 siRNA groups, respectively. In conclusion, our data provides evidence that Mas activation with AVE reduces oxidative stress injury and neuronal apoptosis through Mas/PKA/p-CREB/UCP-2 pathway after SAH. Furthermore, our study indicates that Mas may be a novel therapeutic treatment target in early brain injury of SAH.

AVE0991, a nonpeptide analogue of Ang-(1-7), attenuates aging-related neuroinflammation.

During the aging process, chronic neuroinflammation induced by microglia is detrimental for the brain and contributes to the etiology of several aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a newly identified axis of renin-angiotensin system, ACE2/Ang-(1-7)/MAS1 axis plays a crucial role in modulating inflammatory responses under various pathological conditions. However, its relationship with aging-related neuroinflammation is less studied so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we revealed that the neuroinflammation in the aged brain might be attributed to a decreased level of Ang-(1-7). More importantly, we provided evidence that AVE0991, a nonpeptide analogue of Ang-(1-7), attenuated the aging-related neuroinflammation via suppression of microglial-mediated inflammatory response through a MAS1 receptor-dependent manner. Meanwhile, this protective effect might be ascribed to the M2 activation of microglia induced by AVE0991. Taken together, these findings reveal the association of Ang-(1-7) with the inflammatory response in the aged brain and uncover the potential of its nonpeptide analogue AVE0991 in attenuation of aging-related neuroinflammation.

Effect of agonist of angiotensin-(1-7) on atherogenesis in apolipoprotein E-knockout mice / 中华老年医学杂志

Objective To investigate the effects of agonist of angiotensin-(1-7)(AVE0991) on endothelial function and atherogenesis in apolipoprotein E knockout (ApoE-/-) mice.Methods Eight-week-old ApoE-/-male mice and C57BL/6J male mice were randomly divided into 3 groups:a normal diet control group(ND,n=10),a high-fat diet group(HFD,n=10),and a high-fat diet with AVE0991 0.58 μmol · kg-1 · d-1 group(HFD+ AVE0991,n=10).After 12 weeks of treatment,serum levels of lipids and parameters of endothelial function were measured.Atherosclerotic lesions in aorta roots were detected by Oil Red O staining.CD31 levels in the arterial intima were analyzed by immunohistochemistry.Results AVE0991 had no effects on blood lipids (P ＞ 0.05)but lowered serum levels of nitric oxide in high-fat diet mice(76.8±34.4 μmol/L vs.116.8±33.9 μmol/L,P＜0.05).Also,AVE0991 had no effects on the activity of serum nitric oxide synthase(19.5±5.7 U/ml vs.17.9±3.3 U/ml,P＞0.05)but decreased the activity of serum induced nitric oxide synthase(9.0 ±2.3 U/ml vs.12.7 ± 3.2 U/ml,P ＜0.05) and increased the ratio of phosphorylated endothelial nitric oxide synthase to induced nitric oxide synthase in the vessel wall in high-fat diet mice(0.8±0.2％ vs.0.6 ± 0.2％,P ＜ 0.05).AVE0991 decreased serum levels of C-reactive protein,tumor necrosis factor-α and interleukin-6 (P ＜ 0.05),and decreased the area percentage of atherosclerotic lesions in aorta roots (15.6 ± 3.3 ％ vs.45.4 ± 9.8 ％,P ＜ 0.05) and increased the integrated optical density of CD31 in the arterial intima in high-fat diet mice(54.1±11.0％ vs.28.7±10.6％,P＜0.05)Conclusions AVE0991 can attenuate atherogenesis in ApoE-/-mice fed a high-fat diet,possibly via reducing inflammatory response,regulating the activity of nitric oxide synthases and improving endothelial functions.

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

BACKGROUND AND PURPOSE: AVE 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 APPROACH: We 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 RESULTS: Treatment 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 IMPLICATIONS: AVE 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.