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 1-7 (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.


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.
Graduate Center for Nutritional Sciences, Rm 521b, Wethington Bldg, 900 S Limestone, University of Kentucky, Lexington, KY 40536-0200, USA.
Sean E
SE
Thatcher
Xuan
X
Zhang
Deborah A
DA
Howatt
Hong
H
Lu
Susan B
SB
Gurley
Alan
A
Daugherty
Lisa A
LA
Cassis
D000803:Angiotensin I; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001854:Bone Marrow Cells / Q000201:enzymology* / Q000276:immunology; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000637:transplantation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
D047228:Angiotensin II Type 1 Receptor Blockers; D017077:Culture Media, Conditioned; D016207:Cytokines; D004041:Dietary Fats; D018836:Inflammation Mediators; D010446:Peptide Fragments; D011973:Receptors, LDL; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D019808:Losartan
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