Open AccessToll‐Like Receptor 9 Plays a Pivotal Role in Angiotensin II–Induced Atherosclerosis
Author(s) -
Fukuda Daiju,
Nishimoto Sachiko,
Aini Kunduziayi,
Tanaka Atsushi,
Nishiguchi Tsuyoshi,
KimKaneyama Joori,
Lei XiaoFeng,
Masuda Kiyoshi,
Naruto Takuya,
Tanaka Kimie,
Higashikuni Yasutomi,
Hirata Yoichiro,
Yagi Shusuke,
Kusunose Kenya,
Yamada Hirotsugu,
Soeki Takeshi,
Imoto Issei,
Akasaka Takashi,
Shimabukuro Michio,
Sata Masataka
Publication year - 2019
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.118.010860
Subject(s) - inflammation , medicine , proinflammatory cytokine , angiotensin ii , apolipoprotein e , receptor , tlr9 , endocrinology , immunology , knockout mouse , innate immune system , biology , gene expression , gene , biochemistry , disease , dna methylation
Background Toll‐like receptor ( TLR ) 9 recognizes bacterial DNA , activating innate immunity, whereas it also provokes inflammation in response to fragmented DNA released from mammalian cells. We investigated whether TLR 9 contributes to the development of vascular inflammation and atherogenesis using apolipoprotein E–deficient ( Apoe −/− ) mice. Methods and Results Tlr9 ‐deficient Apoe −/− ( Tlr9 −/− Apoe −/− ) mice and Apoe −/− mice on a Western‐type diet received subcutaneous angiotensin II infusion (1000 ng/kg per minute) for 28 days. Angiotensin II increased the plasma level of double‐stranded DNA, an endogenous ligand of TLR 9, in these mice. Genetic deletion or pharmacologic blockade of TLR 9 in angiotensin II–infused Apoe −/− mice attenuated atherogenesis in the aortic arch ( P <0.05), reduced the accumulation of lipid and macrophages in atherosclerotic plaques, and decreased RNA expression of inflammatory molecules in the aorta with no alteration of metabolic parameters. On the other hand, restoration of TLR 9 in bone marrow in Tlr9 −/− Apoe −/− mice promoted atherogenesis in the aortic arch ( P <0.05). A TLR 9 agonist markedly promoted proinflammatory activation of Apoe −/− macrophages, partially through p38 mitogen‐activated protein kinase signaling. In addition, genomic DNA extracted from macrophages promoted inflammatory molecule expression more effectively in Apoe −/− macrophages than in Tlr9 −/− Apoe −/− macrophages. Furthermore, in humans, circulating double‐stranded DNA in the coronary artery positively correlated with inflammatory features of coronary plaques determined by optical coherence tomography in patients with acute myocardial infarction ( P <0.05). Conclusions TLR 9 plays a pivotal role in the development of vascular inflammation and atherogenesis through proinflammatory activation of macrophages. TLR 9 may serve as a potential therapeutic target for atherosclerosis.