Angiotensin-Converting Enzyme 2 Deficiency in Whole Body or Bone Marrow-Derived Cells Increases Atherosclerosis in Low-Density Lipoprotein Receptor(-/-) Mice

Graduate Center for Nutritional Sciences, Rm 521b, Wethington Bldg, 900 S Limestone, University of Kentucky, Lexington, KY 40536-0200, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 03/2011; 31(4):758-65. DOI: 10.1161/ATVBAHA.110.221614
Source: PubMed


The renin-angiotensin system contributes to atherosclerotic lesion formation. Angiotensin-converting enzyme 2 (ACE2) catabolizes angiotensin II (Ang II) to angiotensin 1-7 (Ang-(1-7)) to limit effects of the renin-angiotensin system. The purpose of this study was to define the role of ACE2 in atherosclerosis.
Male Ace2(-/y) mice in an low-density lipoprotein receptor-deficient background were fed a high-fat diet for 3 months. ACE2 deficiency increased atherosclerotic area (Ace2(+/y), 17 ± 1; Ace2(-/y), 23 ± 2 mm(2), P < 0.002). This increase was blunted by losartan. To determine whether leukocytic ACE2 influenced atherosclerosis, irradiated low-density lipoprotein receptor-deficient male mice were repopulated with bone marrow-derived cells from Ace2(+/y) or Ace2(-/y) mice and fed a high-fat diet for 3 months. ACE2 deficiency in bone marrow-derived cells increased atherosclerotic area (Ace2(+/y), 1.6 ± 0.3; Ace2(-/y), 2.8 ± 0.3 mm(2); P < 0.05). Macrophages from Ace2(-/y) mice exhibited increased Ang II secretion and elevated expression of inflammatory cytokines. Conditioned media from mouse peritoneal macrophages of Ace2(-/y) mice increased monocyte adhesion to human umbilical vein endothelial cells. Incubation of human umbilical vein endothelial cells with Ang II promoted monocyte adhesion, which was blocked by Ang-(1-7). Coinfusion of Ang-(1-7) with Ang II reduced atherosclerosis.
These results demonstrate that ACE2 deficiency in bone marrow-derived cells promotes atherosclerosis through regulation of Ang II/Ang-(1-7) peptides.

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    • "In support of our data, Dong and co-workers[22]showed that ACE2 overexpression enhances plaque stability in a rabbit model of atherosclerosis by reducing macrophage infiltration, decreasing lipid deposition, lowering MMP-3 and MMP-9 activities, and increasing collagen content. Similarly, ACE2 gene deletion increased atherosclerotic vulnerability by increasing the intraplaque inflammatory profile232425. Therefore, the pharmacological activation of ACE2 by diminazene appears to be consistent with the previous studies evaluating ACE2 overexpression or deletion. "

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