The anti-atherosclerotic effect of chronic AT1 receptor blocker treatment also depends on the ACE2/Ang(1−7)/Mas axis

IF 6.9 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Tobias Klersy , Leonie Achner , Benedikt Fels , Flavia Rezende , Melina Lopez , Natalia Alenina , Frauke Spiecker , Ines Stölting , Walter Häuser , Tobias Reinberger , Zouhair Aherrahrou , Carsten Kuenne , Carl Vahldieck , Urte Matschl , Susanne Hille , Michael Bader , Ralf P. Brandes , Oliver J. Müller , Kristina Kusche-Vihrog , Walter Raasch
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Abstract

Blockade of AT1-receptors by telmisartan (TEL) has anti-atherosclerotic efficacy. We investigated to what extent the ACE2/Ang1–7/Mas axis-dependent mechanism contributes to the TEL-induced protection of endothelial function.
Atherosclerosis was induced in C57BL/6 N, Mas-knock out (ko), and Ace2-ko mice by AAV-PCSK9DY (2 ×1011 VG) injections plus Western diet (WD) feeding (12w). Mice were treated (12w) with TEL or vehicle. Controls received no PCSK9DY, chow-feeding, and vehicle-treatment. In the aortae of mice, the plaque burden was determined, RNAseq analyses were performed and functional properties were assessed by quantifying the mechanical properties of the endothelial surface by Atomic Force Microscopy.
Regardless of strain, plaque burden and total cholesterol were increased upon AAV-PCSK9DY+WD but decreased by TEL. Cortical stiffness was also enhanced in all strains by AAV-PCSK9DY+WD but reduced under TEL only in the C57BL/6 N, while remaining still high in both knockout strains. Plasma NO negatively correlated with cortical stiffness in C57BL/6 N, but not in transgenic mice. TNFα plasma levels and aortic MMP12 expression was increased in PCSK9DY/WD vehicle-treated controls and was normalized by TEL in C57BL/6 N but not in Mas-ko and Ace2-ko mice.
We conclude that TEL-induced reduction of endothelial stiffness occurred only in the C57BL/6 N but not in the Mas-ko and Ace2-ko mice. We suggest that the protective TEL effect is partly due to an Ang(1−7)/ACE2/Mas axis mediated mechanism. Since Mmp12 has well-known proatherogenic properties but was not altered in the two transgenic mouse lines, follow-up studies are required to further elucidate the correlation between Mmp12 and the Ang(1−7)/ACE2/Mas axis with respect to atherosclerosis.
慢性AT1受体阻滞剂治疗的抗动脉粥样硬化作用也取决于ACE2/Ang(1−7)/Mas轴
替米沙坦阻断at1受体具有抗动脉粥样硬化的作用。我们研究了ACE2/ Ang1-7 /Mas轴依赖性机制在多大程度上促进了tel诱导的内皮功能保护。AAV-PCSK9DY(2 ×1011 VG)注射加Western diet (WD)喂养(12w)诱导C57BL/6 N、mas敲除(ko)和Ace2-ko小鼠动脉粥样硬化。小鼠分别用TEL或载药治疗(12w)。对照组不给予PCSK9DY,不喂饲料,不进行车辆处理。在小鼠主动脉中,测定斑块负荷,进行RNAseq分析,并通过原子力显微镜定量内皮表面的力学特性来评估功能特性。无论哪种菌株,AAV-PCSK9DY+WD均增加了斑块负担和总胆固醇,而TEL均降低了斑块负担和总胆固醇。所有菌株中,AAV-PCSK9DY+WD均增强了皮质硬度,但TEL仅在C57BL/6 N中降低了皮质硬度,而在两种敲除菌株中均保持较高水平。血浆NO与C57BL/6 N的皮质硬度呈负相关,但在转基因小鼠中无相关。PCSK9DY/WD处理的对照组tnf - α血浆水平和主动脉MMP12表达升高,C57BL/6 N小鼠的TEL正常表达,而Mas-ko和Ace2-ko小鼠则没有。我们得出结论,tel诱导的内皮硬度降低仅发生在C57BL/6 N中,而不发生在Mas-ko和Ace2-ko小鼠中。我们认为TEL的保护作用部分是由于Ang(1−7)/ACE2/Mas轴介导的机制。由于Mmp12具有众所周知的促动脉粥样硬化特性,但在两种转基因小鼠系中未发生改变,因此需要进一步研究Mmp12与Ang(1−7)/ACE2/Mas轴在动脉粥样硬化中的相关性。
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来源期刊
CiteScore
11.90
自引率
2.70%
发文量
1621
审稿时长
48 days
期刊介绍: Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.
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