期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 31, 期 4, 页码 758-U87出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.110.221614
关键词
angiotensin II; atherosclerosis; leukocytes; macrophages; ACE2
资金
- National Institutes of Health [F32 HL095281, R01-HL062846]
- Alaska Kidney Foundation
Objective-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. 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 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. Conclusion-These results demonstrate that ACE2 deficiency in bone marrow-derived cells promotes atherosclerosis through regulation of Ang II/Ang-(1-7) peptides. (Arterioscler Thromb Vasc Biol. 2011;31:758-765.)
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