Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse.
BACKGROUND
Angiotensin-converting enzyme (ACE)2 opposes the actions of angiotensin (Ang) II by degrading it to Ang 1-7.


OBJECTIVE
Given the important role of Ang II/Ang 1-7 in atherogenesis, we investigated the impact of ACE2 deficiency on the development of atherosclerosis.


RESULTS
C57Bl6, Ace2 knockout (KO), apolipoprotein E (ApoE) KO and ApoE/Ace2 double KO mice were followed until 30 weeks of age. Plaque accumulation was increased in ApoE/Ace2 double KO mice when compared to ApoE KO mice. This was associated with increased expression of adhesion molecules and inflammatory cytokines, including interleukin-6, monocyte chemoattractant protein-1, and vascular cell adhesion molecule-1, and an early increase in white cell adhesion across the whole aortae on dynamic flow assay. In the absence of a proatherosclerotic (ApoE KO) genotype, ACE2 deficiency was also associated with increased expression of these markers, suggesting that these differences were not an epiphenomenon. ACE inhibition prevented increases of these markers and atherogenesis in ApoE/ACE2 double KO mice. Bone marrow macrophages isolated from Ace2 KO mice showed increased proinflammatory responsiveness to lipopolysaccharide and Ang II when compared to macrophages isolated from C57Bl6 mice. Endothelial cells isolated from Ace2 KO mice also showed increased basal activation and elevated inflammatory responsiveness to TNF-α. Similarly, selective inhibition of ACE2 with MLN-4760 also resulted in a proinflammatory phenotype with a physiological response similar to that observed with exogenous Ang II (10(-7) mol/L).


CONCLUSIONS
Genetic Ace2 deficiency is associated with upregulation of putative mediators of atherogenesis and enhances responsiveness to proinflammatory stimuli. In atherosclerosis-prone ApoE KO mice, these changes potentially contribute to increased plaque accumulation. These findings emphasize the potential utility of ACE2 repletion as a strategy to reduce atherosclerosis.
Thomas
Merlin C
MC
Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
Pickering
Raelene J
RJ
Tsorotes
Despina
D
Koitka
Audrey
A
Sheehy
Karen
K
Bernardi
Stella
S
Toffoli
Barbara
B
Nguyen-Huu
Thu-Phuc
TP
Head
Geoffrey A
GA
Fu
Yi
Y
Chin-Dusting
Jaye
J
Cooper
Mark E
ME
Tikellis
Chris
C
D000085962:Angiotensin-Converting Enzyme 2; D000809:Angiotensins / Q000097:blood; D000818:Animals; D001018:Aortic Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D001794:Blood Pressure / Q000502:physiology; D002461:Cell Line, Transformed; D042783:Endothelial Cells / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism; D014657:Vasculitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*
D000809:Angiotensins; D001057:Apolipoproteins E; D018836:Inflammation Mediators; D008055:Lipids; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2