Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice
Hong Lu, … , Lisa A. Cassis, Alan Daugherty
Hong Lu, … , Lisa A. Cassis, Alan Daugherty
Published February 14, 2008
Citation Information: J Clin Invest. 2008;118(3):984-993. https://doi.org/10.1172/JCI32970.
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Research Article Cardiology

Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice

Abstract

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor–deficient (Ldlr–/–) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr–/– mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice.

Authors

Hong Lu, Debra L. Rateri, David L. Feldman, Richard J. Charnigo Jr., Akiyoshi Fukamizu, Junji Ishida, Elizabeth G. Oesterling, Lisa A. Cassis, Alan Daugherty

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Figure 7

Renin deficiency in mouse macrophages markedly reduced monocyte adhesion to endothelial cells.

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Renin deficiency in mouse macrophages markedly reduced monocyte adhesion...
(A) AngII resulted in increased THP-1 monocyte adhesion to endothelial cells. The adhesion assay was performed by coincubation of 10–7 M AngII with HUVECs for 18 hours. Values (mean ± SEM) represent cell number of each well relative to vehicle per HPF (n = 4 per group). *P = 0.009 versus vehicle. (B) The AT1 receptor antagonist losartan inhibited AngII-induced THP-1 monocyte adhesion to endothelial cells. The adhesion assay was performed by coincubation of 10–7 M AngII and 10–6 M losartan. Losartan was added 2 hours prior to the addition of AngII to cultured HUVECs. Values (mean ± SEM) represent cell number of each well relative to losartan per HPF (n = 3 per group). *P < 0.001 versus AngII. (C) Renin deficiency resulted in decreased THP-1 monocyte adhesion to HUVECs. Cultured peritoneal macrophages from renin+/+ or renin–/– mice were coincubated with HUVECs for 24 hours, and an adhesion assay was then performed. Values (mean ± SEM) represent cell number of each well relative to renin–/– per HPF (n = 4 per group). *P = 0.03 versus renin+/+.