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

Blockade of AT 1 -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 DY (2 ×10 11 VG) injections plus Western diet (WD) feeding (12w). Mice were treated (12w) with TEL or vehicle. Controls received no PCSK9 DY , 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 DY +WD but decreased by TEL. Cortical stiffness was also enhanced in all strains by AAV-PCSK9 DY +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 DY /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. indicating that a TNFα-dependent mechanism upregulates expression of MMP12 and NO, thus contributing to increase in cortical stiffness. It is further concluded that increased cortical stiffness leads to impaired vasodilation and thus promotes the development of atherosclerosis. However, since we did not perform any experiments on vasodilation, this conclusion is in italics to emphasize that it is based more on findings in the literature (see discussion) and less on experimental data. TEL counterregulated these pathways via at least partial stimulation of the ACE2/Ang(1−7)/Mas axis. • Endothelial stiffness worsens in atherosclerotic mice. • MMP12 and NO are regulated downstream of increased TNFα, contributing to higher cortical stiffness. • Telmisartan improves endothelial stiffness in mice prone to atherosclerosis. • Telmisartan does not improve endothelial stiffness in Mas-ko and Ace2-ko mice. • The protection effect of telmisartan is partly mediated by the Ang(1−7)/ACE2/Mas pathway.