Background
AVE 0991 is a Nonpeptide Mimic of the Effects of Angiotensin-(1-7) on the Endothelium. AVE 0991 and unlabeled Ang-(1-7) competed for high-affinity binding of [125I]-Ang-(1-7) to bovine aortic endothelial cell membranes with IC50 values of 21+/-35 and 220+/-280 nM, respectively[4].
AVE 0991 displaced the binding of 125I-Ang-(1-7) in Mas-transfected monkey kidney cells (COS) cells (IC50=4.75x10(-8) mol/L) and of rhodamine-Ang-(1-7) in Mas-transfected Chinese hamster ovary (CHO) cells. It also produced NO release in Mas-transfected CHO cells blocked by A-779 but not by angiotensin II type-1 (AT1) and AT2 antagonists[7].
AVE 0991 attenuates oxidative stress and neuronal apoptosis via 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[2].Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats[1]. Enhanced Ang II and attenuated Ang-(1-7) levels were also observed in the liver tissue of heatstroke rats, which were consistent with their receptors and converting enzymes. Hepatic damage associated with increased ROS and protein expression levels of NOX4, NLRP3, caspase-1, and IL-1β was attenuated by AVE 0991, an analogue of Ang-(1-7) [3]. Oral treatment with AVE 0991 reduces blood-pressure cardiac remodeling and improves baroreflex sensitivity in 2K1C renovascular hypertensive rats[5]. AVE 0991 prevented AngII-inducing myocardial hypertrophy in a dose-dependent fashion, a process that may be associated with the inhibition of TGF-beta1/Smad2 signaling[6].
参考文献:
[1]. Mo J, Enkhjargal B, et,al. AVE 0991 attenuates oxidative stress and neuronal apoptosis via Mas/PKA/CREB/UCP-2 pathway after subarachnoid hemorrhage in rats. Redox Biol. 2019 Jan;20:75-86. doi: 10.1016/j.redox.2018.09.022. Epub 2018 Sep 28. PMID: 30296700; PMCID: PMC6174866.
[2]. Ma Y, Huang H, et,al. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress. Biochem Biophys Res Commun. 2016 Jun 10;474(4):621-625. doi: 10.1016/j.bbrc.2015.09.050. Epub 2015 Sep 25. PMID: 26403967.
[3]. Zhang M, Zhu X, et,al. AVE 0991 Attenuates Pyroptosis and Liver Damage after Heatstroke by Inhibiting the ROS-NLRP3 Inflammatory Signalling Pathway. Biomed Res Int. 2019 Aug 19;2019:1806234. doi: 10.1155/2019/1806234. PMID: 31531346; PMCID: PMC6720052.
[4]. Wiemer G, Dobrucki LW, et,al. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. Hypertension. 2002 Dec;40(6):847-52. doi: 10.1161/01.hyp.0000037979.53963.8f. PMID: 12468568.
[5]. Cunha TM, Lima WG, et,al.The nonpeptide ANG-(1-7) mimic AVE 0991 attenuates cardiac remodeling and improves baroreflex sensitivity in renovascular hypertensive rats. Life Sci. 2013 Mar 12;92(4-5):266-75. doi: 10.1016/j.lfs.2012.12.008. Epub 2013 Jan 16. PMID: 23333828.
[6]. He JG, Chen SL, et,al. The nonpeptide AVE0991 attenuates myocardial hypertrophy as induced by angiotensin II through downregulation of transforming growth factor-beta1/Smad2 expression. Heart Vessels. 2010 Sep;25(5):438-43. doi: 10.1007/s00380-009-1213-7. Epub 2010 Jul 31. PMID: 20676968.
[7]. Pinheiro SV, Sim?es e Silva AC, et,al. Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension. 2004 Oct;44(4):490-6. doi: 10.1161/01.HYP.0000141438.64887.42. Epub 2004 Aug 23. PMID: 15326087.
AVE 0991 是血管紧张素 (1-7) 对内皮细胞作用的非肽模拟物。 AVE 0991 和未标记的 Ang-(1-7) 竞争 [125I]-Ang-(1-7) 与牛主动脉内皮细胞膜的高亲和力结合，IC50 值为 21+/-35 和 220+/-280 nM，分别[4].
AVE 0991 在 Mas 转染的猴肾细胞 (COS) 细胞中取代了 125I-Ang-(1-7) 的结合 (IC50=4.75x10 (-8) mol/L) 和罗丹明-Ang-(1-7) 在 Mas 转染的中国仓鼠卵巢 (CHO) 细胞中。它还在被 A-779 而不是血管紧张素 II 型 1 (AT1) 和 AT2 拮抗剂阻断的 Mas 转染的 CHO 细胞中产生 NO 释放[7]。
AVE 0991减轻氧化应激和神经元凋亡，通过对小鼠进行主动脉束带以诱导心脏肥大，然后给予 AVE 0991（20 mg kg.day (-1)）4 周。结果表明，AVE 0991 减少了左心室肥大并改善了心脏功能，其特点是左心室重量和左心室舒张末期直径减少，射血分数增加。此外，AVE 0991显着下调平均肌细胞直径并减弱肥大标志物的基因表达[2].大鼠蛛网膜下腔出血后Mas/PKA/CREB/UCP-2通路[ 1]。在中暑大鼠的肝组织中也观察到增强的 Ang II 和减弱的 Ang-(1-7) 水平，这与其受体和转化酶一致。与 ROS 和 NOX4、NLRP3、caspase-1 和 IL-1β 蛋白表达水平升高相关的肝损伤；被 AVE 0991 减弱，AVE 0991 是 Ang-(1-7) [3] 的类似物。口服 AVE 0991 可降低 2K1C 肾血管性高血压大鼠的血压心脏重塑并提高压力反射敏感性[5]。 AVE 0991 以剂量依赖性方式阻止 AngII 诱导的心肌肥大，这一过程可能与抑制 TGF-beta1/Smad2 信号转导有关[6]。
Protocol
| Kinase experiment [1]: |
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Preparation Method
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Competition experiments with increasing concentrations of AVE 0991 and unlabeled Ang-(1 7) were performed in the presence of 10 nmol/L [125I]-Ang-(1-7). Assays were terminated by vacuum filtration ( 15 mm Hg) over Durapore filters (0.65 |?, Opak 96-well plates, Millipore) presoaked with 1% BSA.
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Applications
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AVE 0991 and unlabeled Ang-(1-7) competed the specific binding of [125I]-Ang-(1-7), with IC50 values of 21 ?à35 and 220 ?à 280 nmol/L, respectively (each n=3). The Ang-(1-7) analogue [D-Ala7]-Ang-(1 7) totally competed the specific binding of [125I]-Ang-(1-7), with an IC50 value of 0.41 ?à3.0 |?ol/L (n=3).
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| Cell experiment [2]: |
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Cell lines
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Chinese hamster ovary (CHO) cells
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Preparation Method
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Binding of rhodamine Ang-(1-7) in Mas-transfected CHO cells was performed under similar conditions using 2*10 -9 mol/L rhodamine-labeled Ang-(1-7) in the presence or absence of AVE 0991(10 -6 mol/L), CV11974, or PD123319
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Reaction Conditions
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AVE 0991 (10-6 mol/L)
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Applications
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AVE 0991 displaced the binding of 125I-Ang-(1-7) in Mas-transfected monkey kidney cells (COS) cells (IC50=4.75x10(-8) mol/L) and of rhodamine-Ang-(1-7) in Mas-transfected Chinese hamster ovary (CHO) cells. It also produced NO release in Mas-transfected CHO cells blocked by A-779 but not by angiotensin II type-1 (AT1) and AT2 antagonists.
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| Animal experiment [3]: |
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Animal models
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Male C57BL/6J mice (8¨C10 weeks old; 24¨C26 g)
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Preparation Method
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Twenty-four h after ligation, the surviving mice were randomly divided into four groups: 1) sham-operated group, 2) vehicle-treated AB group (vehicle-treated group ), 3) AB mice treated with AVE 0991 ( AVE 0991 group ). AVE 0991 group was administered orally once a day at AVE 0991 (20 mg kg/day) for 4 weeks while isovolumic sodium chloride was administrated in the same manner for the sham-operated and vehicle-treated group.
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Dosage form
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AVE 0991 (20 mg kg/day) for 4 weeks
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Applications
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AVE 0991 treatment could attenuate cardiac hypertrophy and improve heart function, which may be due to reduce oxidative stress./p>
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参考文献:
[1]. Wiemer G, Dobrucki LW,et,al. AVE 0991, a nonpeptide mimic of the effects of angiotensin-(1-7) on the endothelium. Hypertension. 2002 Dec;40(6):847-52. doi: 10.1161/01.hyp.0000037979.53963.8f. PMID: 12468568.
[2]. Pinheiro SV, Sim?es e Silva AC, et,al.Nonpeptide AVE 0991 is an angiotensin-(1-7) receptor Mas agonist in the mouse kidney. Hypertension. 2004 Oct;44(4):490-6. doi: 10.1161/01.HYP.0000141438.64887.42. Epub 2004 Aug 23. PMID: 15326087.
[3]. Ma Y, Huang H, et,al. AVE 0991 attenuates cardiac hypertrophy through reducing oxidative stress. Biochem Biophys Res Commun. 2016 Jun 10;474(4):621-625. doi: 10.1016/j.bbrc.2015.09.050. Epub 2015 Sep 25. PMID: 26403967.
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