Angiotensin-converting enzyme 2 deficiency in whole body or bone marrow-derived cells increases atherosclerosis in low-density lipoprotein receptor -/- mice

Sean E. Thatcher, Xuan Zhang, Deborah A. Howatt, Hong Lu, Susan B. Gurley, Alan Daugherty, Lisa A. Cassis

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)758-765
Number of pages8
JournalArteriosclerosis, thrombosis, and vascular biology
Volume31
Issue number4
DOIs
StatePublished - Apr 2011

Keywords

  • ACE2
  • angiotensin II
  • atherosclerosis
  • leukocytes
  • macrophages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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