Renin inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques

Hongxian Wu, Xian Wu Cheng, Lina Hu, Chang Ning Hao, Mutsuharu Hayashi, Kyosuke Takeshita, Mohammad Shoaib Hamrah, Guo Ping Shi, Masafumi Kuzuya, Toyoaki Murohara

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

Objective: The interaction between the renin-angiotensin system and toll-like receptors (TLRs) in the pathogenesis of advanced atherosclerotic plaques is not well understood. We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E-deficient (ApoE-/-) mice with a special focus on plaque neovessel formation. Methods and results: Four-wk-old ApoE-/- mice were fed a high-fat diet for 8wks, and the mice were randomly assigned to one of three groups and administered a vehicle, hydralazine, or aliskiren for an additional 12wks. Aliskiren reduced the atherosclerotic plaque area and plaque neovessel density. It increased the plaque collagen and elastin contents, and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S (CatS) protein. Aliskiren also decreased the levels of AT1R, gp91phox, TLR2, monocyte chemotactic protein-1, and CatS mRNAs in the aortic roots. Hydralazine had no beneficial vascular effects, although its administration resulted in the same degree of blood pressure reduction as aliskiren. CatS deficiency mimicked the aliskiren-mediated vasculoprotective effect in the ApoE-/- mice, but aliskiren showed no further benefits in ApoE-/- CatS-/- mice. Invitro, TLR2 silencing reduced CatS expression induced by angiotensin II. Moreover, aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action invitro or/and exvivo. Conclusion: Renin inhibition appears to inhibit advanced plaque neovessel formation in ApoE-/- mice and to decrease the vascular inflammatory action and extracellular matrix degradation, partly by reducing AT1R/TLR2-mediated CatS activation and activity, thus regressing advanced atherosclerosis.

Original languageEnglish
Pages (from-to)739e747-747
JournalAtherosclerosis
Volume237
Issue number2
DOIs
Publication statusPublished - 01-12-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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