Angiotensin-Converting Enzyme 2 Deficiency in Whole Body or Bone Marrow–Derived Cells Increases Atherosclerosis in Low-Density Lipoprotein Receptor−/− Mice
Objective—The renin-angiotensin system contributes to atherosclerotic lesion formation. Angiotensin-converting enzyme 2 (ACE2) catabolizes angiotensin II (Ang II) to angiotensin 1 to 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.
Methods and Results—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 mm2, 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 mm2; P<0.05). Macrophages from Ace2−/y mice exhibited increased Ang II secretion and elevated expression of inflammatory cytokines. Conditioned media from MPMs 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.
Conclusion—These results demonstrate that ACE2 deficiency in bone marrow–derived cells promotes atherosclerosis through regulation of Ang II/Ang-(1–7) peptides.
- Received July 9, 2010.
- Accepted January 5, 2011.
- © 2011 American Heart Association, Inc.