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.

Aliskiren Accumulates in Renin Secretory Granules and Binds Plasma Prorenin

“…In vivo, interference with the negative feedback loop would have been proposed to explain a rise in (pro)renin. 2 However, because we were unable to demonstrate angiotensinogen synthesis by these cells, this explanation cannot be applied here. In fact, incubation with either captopril (10 mol/L) or the Ang II type 1 receptor antagonist eprosartan (1 mol/L) for 7 days did not increase renin (nϭ3; data not shown).…”

“…1,2 Whether they also increase kidney renin is still being debated. [1][2][3] The rise in blood plasma has been suggested to be larger than during other types of RAS blockade, 4 either because the degree of RAS blockade is superior during renin inhibition 5 and/or because renin inhibitors increase the half-life of renin. 6 It may also be an artifact, because renin inhibitors "activate" the precursor of renin, prorenin ( Figure 1).…”

Aliskiren Reduces Myocardial Ischemia–Reperfusion Injury by a Bradykinin B 2 Receptor– and Angiotensin AT 2 Receptor–Mediated Mechanism

“…In animal models, aliskiren reduces myocardial infarct size and left ventricular remodeling after myocardial infarction, [5][6][7][8] increases nitric oxide bioavailability, 9 and inhibits atherosclerosis. [9][10][11] Recently, we reported that aliskiren increases tissue kallikrein and bradykinin levels in the rat heart at plasma levels within the therapeutic range in patients. 12 Both the dose-response and time course of the aliskiren-induced increases in cardiac bradykinin levels suggested that these actions of aliskiren were independent of renin inhibition.…”

Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells

“…These results suggested that blockade of AT1 receptor in BM cells might have inhibitory effects on atherosclerosis. In contrast, little or no changes of atherosclerosis in LDL receptor KO mice by transplantation with BM from AT1a receptor KO mice are also reported 36,37 and these reports suggest the ameliorative role of AT1 receptor blockade in vascular cells for the ARB-mediated atherosclerosis inhibition. In accordance with the latter reports, our results strongly suggest that the beneficial effects of ARB in end-organ injuries are attributed to the blockade of AT1 receptor expressed in the end organs, but not in BMDCs (Figures 2 and 4).…”