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

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-PCSK9^DY (2 ×10¹¹ 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.