| Summary: | Circulating levels of soluble ACE2 are increased by diabetes. Although this increase is associated with the presence and severity of cardiovascular disease, the specific role of soluble ACE2 in atherogenesis is unclear. Previous studies suggested that, like circulating ACE, soluble ACE2 plays a limited role in vascular homeostasis. To challenge this hypothesis, we aimed to selectively increase circulating ACE2 and measure its effects on angiotensin II dependent atherogenesis. Firstly, in <i>Ace2/ApoE</i> DKO mice, restoration of circulating ACE2 with recombinant murine soluble (rmACE2<sub>19-613</sub>; 1 mg/kg/alternate day IP) reduced plaque accumulation in the aortic arch, suggesting that the phenotype may be driven as much by loss of soluble ACE2 as the reduction in local ACE2. Secondly, in diabetic <i>ApoE</i> KO mice, where activation of the renin angiotensin system drives accelerated atherosclerosis, rmACE2<sub>19-613</sub> also reduced plaque accumulation in the aorta after 6 weeks. Thirdly, to ensure consistent long-term delivery of soluble ACE2, an intramuscular injection was used to deliver a DNA minicircle encoding ACE2<sub>19-613</sub>. This strategy efficiently increased circulating soluble ACE2 and reduced atherogenesis and albuminuria in diabetic <i>ApoE</i> KO mice followed for 10 weeks. We propose that soluble ACE2 has independent vasculoprotective effects. Future strategies that increase soluble ACE2 may reduce accelerated atherosclerosis in diabetes and other states in which the renin angiotensin system is upregulated.
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