Klersy Tobias, Achner Leonie, Fels Benedikt, Rezende Flavia, Lopez Melina, Alenina Natalia, Spiecker Frauke, Stölting Ines, Häuser Walter, Reinberger Tobias, Aherrahrou Zouhair, Kuenne Carsten, Vahldieck Carl, Matschl Urte, Hille Susanne, Bader Michael, Brandes Ralf P, Müller Oliver J, Kusche-Vihrog Kristina, Raasch Walter
Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Germany.
Institute for Physiology, University Lübeck, Germany.
Biomed Pharmacother. 2025 May;186:117990. doi: 10.1016/j.biopha.2025.117990. Epub 2025 Mar 18.
Blockade of AT-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-PCSK9 (2 ×10 VG) injections plus Western diet (WD) feeding (12w). Mice were treated (12w) with TEL or vehicle. Controls received no PCSK9, 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-PCSK9+WD but decreased by TEL. Cortical stiffness was also enhanced in all strains by AAV-PCSK9+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 PCSK9/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.
替米沙坦（TEL）阻断AT受体具有抗动脉粥样硬化功效。我们研究了ACE2/Ang1-7/Mas轴依赖性机制在多大程度上有助于TEL诱导的内皮功能保护。通过注射腺相关病毒PCSK9（2×10 VG）并给予西方饮食（WD）喂养（12周），在C57BL/6 N、Mas基因敲除（ko）和Ace2基因敲除小鼠中诱导动脉粥样硬化。小鼠接受TEL或赋形剂治疗（12周）。对照组未接受PCSK9，给予普通饲料喂养，并接受赋形剂治疗。在小鼠主动脉中，测定斑块负荷，进行RNA测序分析，并通过原子力显微镜量化内皮表面的力学性能来评估功能特性。无论品系如何，AAV-PCSK9+WD处理后斑块负荷和总胆固醇均增加，但TEL可使其降低。AAV-PCSK9+WD也使所有品系的皮质硬度增强，但仅在C57BL/6 N小鼠中，TEL可使其降低，而在两种基因敲除品系中仍保持较高水平。在C57BL/6 N小鼠中，血浆NO与皮质硬度呈负相关，但在转基因小鼠中并非如此。在PCSK9/WD赋形剂处理的对照组中，TNFα血浆水平和主动脉MMP12表达增加，TEL可使其在C57BL/6 N小鼠中恢复正常，但在Mas-ko和Ace2-ko小鼠中则不能。我们得出结论，TEL诱导的内皮硬度降低仅发生在C57BL/6 N小鼠中，而在Mas-ko和Ace2-ko小鼠中未发生。我们认为TEL的保护作用部分归因于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品系中未发生改变，因此需要进一步的后续研究来阐明Mmp12与Ang(1-7)/ACE2/Mas轴在动脉粥样硬化方面的相关性。
