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血管紧张素IV通过可变血管紧张素受体刺激对腹主动脉瘤的剂量依赖性双向作用。

Dose-Dependent Bidirectional Effect of Angiotensin IV on Abdominal Aortic Aneurysm via Variable Angiotensin Receptor Stimulation.

作者信息

Kong Jing, Zhang Kai, Meng Xiao, Zhang Yun, Zhang Cheng

机构信息

From the The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, and The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.

出版信息

Hypertension. 2015 Sep;66(3):617-26. doi: 10.1161/HYPERTENSIONAHA.115.05482. Epub 2015 Aug 3.

Abstract

Angiotensin IV (Ang IV), as an effector peptide of the rennin-angiotensin system, possesses many biological properties yet not completely known. In this study, we aimed to investigate the role of Ang IV in the development of Ang II-induced abdominal aortic aneurysm (AAA) in apolipoprotein E-knockout mice. We used Ang II infusion to induce AAA, and animals were treated with Ang II (1.44 mg/kg per day) plus no treatment, Ang II (1.44 mg/kg per day) plus low-, medium-, and high-dose Ang IV (0.72, 1.44, and 2.88 mg/kg per day, respectively). The incidence of AAA was 87.5%, 66.7%, 37.5%, and 83.3% in the no treatment, the low-, medium-, or high-dose Ang IV group, respectively. Compared with the no treatment group, medium-dose Ang IV treatment markedly reduced macrophage infiltration; levels of proinflammatory cytokines, including monocyte chemoattractant protein 1, interleukin 6, and intercellular adhesion molecule 1; the expression and activity of metalloproteinases 2 and 9; but increased smooth muscle cells, and collagen content in AAA. However, high-dose Ang IV treatment did not have obvious protective effect. The beneficial effect of medium-dose Ang IV may be contributed to the stimulation of type 4 angiotensin receptor (AT4R) and AT2R with suppression of AT1R, activation of Akt, and inhibition of nuclear factor-κB, as these beneficial effects were largely reversed by cotreatment with the AT4R antagonist divalinal-Ang IV in Ang II-infused mice or with the Akt inhibitor A6730 in Ang II-stimulated human smooth muscle cells. Therefore, medium dose of Ang IV may provide a novel and promising approach to the treatment of AAA.

摘要

血管紧张素IV(Ang IV)作为肾素-血管紧张素系统的一种效应肽,具有许多尚未完全明确的生物学特性。在本研究中,我们旨在探讨Ang IV在载脂蛋白E基因敲除小鼠中Ang II诱导的腹主动脉瘤(AAA)发展过程中的作用。我们采用输注Ang II诱导AAA,将动物分为以下几组进行处理:单纯给予Ang II(每天1.44 mg/kg)不做其他处理、Ang II(每天1.44 mg/kg)加低、中、高剂量Ang IV(分别为每天0.72、1.44和2.88 mg/kg)。未处理组、低剂量Ang IV组、中剂量Ang IV组和高剂量Ang IV组的AAA发生率分别为87.5%、66.7%、37.5%和83.3%。与未处理组相比,中剂量Ang IV处理显著减少了巨噬细胞浸润;降低了促炎细胞因子水平,包括单核细胞趋化蛋白1、白细胞介素6和细胞间黏附分子1;减少了金属蛋白酶2和9的表达及活性;但增加了AAA中的平滑肌细胞数量和胶原蛋白含量。然而,高剂量Ang IV处理没有明显的保护作用。中剂量Ang IV的有益作用可能归因于对4型血管紧张素受体(AT4R)和AT2R的刺激,同时抑制AT1R,激活Akt并抑制核因子-κB,因为在输注Ang II的小鼠中与AT4R拮抗剂二缬氨酰-Ang IV共同处理或在Ang II刺激的人平滑肌细胞中与Akt抑制剂A6730共同处理后,这些有益作用大多被逆转。因此,中剂量的Ang IV可能为AAA的治疗提供一种新的、有前景的方法。

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