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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    • ". Initial studies examined ACE2 activity in the stromal vascular fraction (SVF) isolated from adipose tissues of male C57BL/6 mice (2 months of age; N = 10 /group) fed a low fat (LF; 10% kcal as fat, D12450, Research Diets Inc, New Brunswick, NJ) or high fat (HF, 60% kcal as fat, D12492, Research Diets Inc, New Brunswick, NJ) diet for 16 weeks. For bone marrow transplantation, C57BL/6 male mice (2 months of age) were pretreated with antibiotic water (sulfatrim, 4 μg/mL) for 1 week prior to irradiation [2] [14]. Bone marrow was extracted from the tibias and femurs of Ace2 +/y or Ace2 −/ y male mice (2 months of age) and injected into gamma-irradiated recipient C57BL/6 males (N = 15 mice/donor genotype) at a dose of 10 7 cells per mouse. "
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