Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice
Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice
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DOI：
10.1172/jci32970
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发表时间：
2008-03-01
影响因子：
15.9
通讯作者：
Daugherty, Alan
中科院分区：
文献类型：
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作者：
Lu, Hong;Rateri, Debra L.;Daugherty, Alan
由于涉及多个肽和受体，肾素血管紧张素系统（RAS）在动脉粥样硬化中的作用是复杂的。肾素是所有血管紧张素肽产生的限速酶。为了确定肾素抑制剂对动脉粥样硬化的影响，我们给脂肪喂养的LDL受体缺陷（Ldlr（-/-））小鼠施用了新的肾素抑制剂阿利吉仑，剂量范围很广。肾素抑制导致主动脉弓和根部的动脉粥样硬化病变尺寸显著减小。随后的研究表明，培养的巨噬细胞表达RAS的所有成分。为了确定巨噬细胞源性血管紧张素在动脉粥样硬化发展中的作用，我们将缺乏肾素的骨髓移植到辐照过的Ldlr-/-小鼠中，观察到动脉粥样硬化病变的大小显著减少。在类似的实验中，移植缺乏血管紧张素II 1a型受体的骨髓未能影响病变的发展。我们的结论是，巨噬细胞中的肾素依赖性血管紧张素生产不起作用的自分泌/旁分泌的方式。此外，体外研究表明，与表达肾素的巨噬细胞共培养增强了单核细胞与内皮细胞的粘附。因此，尽管先前的工作表明血管紧张素肽对动脉粥样硬化的作用相互矛盾，但我们发现，肾素抑制能显著降低小鼠病变的发展。
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.