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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引用次数: 0

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.
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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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