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

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.

CONCLUSIONS:

These results demonstrate that ACE2 deficiency in bone marrow-derived cells promotes atherosclerosis through regulation of Ang II/Ang-(1-7) peptides.

• Authors: Sean E Thatcher, Xuan Zhang, Deborah A Howatt, Hong Lu, Susan B Gurley, Alan Daugherty, Lisa A Cassis
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 4 Pg. 758-65 (Apr 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21252069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Culture Media, Conditioned
• Cytokines
• Dietary Fats
• Inflammation Mediators
• Peptide Fragments
• Receptors, LDL
• Angiotensin II
• Angiotensin I
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• angiotensin I (1-7)
• Losartan

Topics

• Angiotensin I
• Angiotensin II (metabolism, pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Angiotensin-Converting Enzyme 2
• Animals
• Atherosclerosis (enzymology, genetics, immunology, pathology, prevention & control)
• Bone Marrow Cells (enzymology, immunology)
• Bone Marrow Transplantation
• Cell Adhesion
• Cells, Cultured
• Coculture Techniques
• Culture Media, Conditioned (metabolism)
• Cytokines (metabolism)
• Dietary Fats
• Disease Models, Animal
• Endothelial Cells (immunology)
• Humans
• Inflammation Mediators (metabolism)
• Losartan (pharmacology)
• Macrophages (enzymology, immunology, transplantation)
• Male
• Mice
• Mice, Knockout
• Monocytes (immunology)
• Peptide Fragments (metabolism, pharmacology)
• Peptidyl-Dipeptidase A (deficiency, genetics)
• Receptors, LDL (deficiency, genetics)