Renin Inhibition Reduces Hypercholesterolemia-Induced Atherosclerosis in Mice

Authors

Hong Lu, University of KentuckyFollow
Debra L. Rateri, University of KentuckyFollow
David L. Feldman, Novartis Institutes for Biomedical Research
Richard Charnigo, University of KentuckyFollow
Akiyoshi Fukamizu, University of Tsukuba, Japan
Junji Ishida, University of Tsukuba, Japan
Elizabeth Grace Oesterling, University of KentuckyFollow
Lisa A. Cassis, University of KentuckyFollow
Alan Daugherty, University of KentuckyFollow

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.

Document Type

Article

Publication Date

3-3-2008

Notes/Citation Information

Published in The Journal of Clinical Investigation, v. 118, no. 3, p. 984-993.

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Digital Object Identifier (DOI)

http://dx.doi.org/10.1172/JCI32970

Repository Citation

Lu, Hong; Rateri, Debra L.; Feldman, David L.; Charnigo, Richard; Fukamizu, Akiyoshi; Ishida, Junji; Oesterling, Elizabeth Grace; Cassis, Lisa A.; and Daugherty, Alan, "Renin Inhibition Reduces Hypercholesterolemia-Induced Atherosclerosis in Mice" (2008). Saha Cardiovascular Research Center Faculty Publications. 10.
https://uknowledge.uky.edu/cvrc_facpub/10