P157Nitroso-redox imbalance contribute to vascular dysfunction and elevated blood pressure in ACE2-deficient mice

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Abstract

Purpose

Angiotensin-converting enzyme 2 (ACE2) is the main enzyme responsible for the degradation of Ang II and generation of Ang-(1-7), peptides which play critical roles in the regulation of blood pressure (BP) and endothelial function. The aim of the present study was to evaluate the effects of chronic Ang-(1-7) treatment and AT1 receptor blockage by losartan on BP in ACE2-deficient (ACE2-/-) mice and to assess the endothelial function and the vascular redox balance in these animals.

Methods and Results

The study was conducted in 20 week-old ACE2-/- male mice on C57Bl/6 background. Telemetric blood pressure measurements confirmed an increase in mean arterial pressure (MAP) in these mice (ACE2-/-: 112.5 ± 3.3 vs C57Bl/6: 105.6 ± 2.3 mmHg, p < 0.01). Chronic Ang-(1-7) infusion led to a 2 mmHg decrease in BP in both ACE2-/- and C57Bl/6 animals, whereas the BP lowering effect of losartan was more pronounced in ACE2-/- than in control animals (MAP post-losartan: ACE2-/-: 101.8 ± 1.9 vs C57Bl/6: 101.7 ± 2.6). Endothelial function was evaluated by measuring changes in MAP in response to bolus intra-aortic acetylcholine (ACh) and sodium nitroprusside (SNP) administration. The endothelium-dependent vascular reactivity was impaired in ACE2-/- mice compared to C57Bl/6 animals (Fig. 1, p < 0.001). ACE2-/- mice presented a lowered plasma and urine nitrite concentration, and reduced aorta NO levels. Lipid peroxidation was significantly increased and superoxide dismutase activity was decreased in the aorta homogenate of ACE2-/- mice in comparison to controls, indicating impaired antioxidant capacity in these animals.

Conclusion

These data demonstrate that oxidative stress and NO imbalance, induced by increased local Ang II levels may cause elevated blood pressure and endothelial dysfunction in ACE2-/- mice.

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