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Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice

Title
Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice
Authors
Jung Y.Y.Kim K.C.Park M.H.Seo Y.Park H.Chang J.Hwang D.Y.Han S.B.Kim S.Son D.J.Hong J.T.
Ewha Authors
장준
SCOPUS Author ID
장준scopus
Issue Date
2018
Journal Title
Theranostics
ISSN
1838-7640JCR Link
Citation
Theranostics vol. 8, no. 3, pp. 749 - 766
Keywords
Alzheimer's diseasesAmyloid precursor proteinAtherosclerosisChitinase-3-like-1Endothelial cellsmicroRNA 342-3p
Publisher
Ivyspring International Publisher
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Although the important role of amyloid precursor protein (APP) in vascular diseases associated with Alzheimer's disease (AD) has been demonstrated, the underlying molecular mechanisms and physiological consequences are unclear. We aimed to evaluate vascular inflammation and atherosclerosis in Swedish mutant of human APP transgenic (APPsw-Tg) and ApoE-/-/APPsw-Tg mice. We also aimed to explore the mechanisms underlying any changes observed in these mice compared with non-Tg controls. Methods: The transgenic and non-Tg mouse strains were subjected to partial ligation of the left carotid artery to induce atherosclerotic changes, which were measured using histological approaches, immunohistochemistry, quantitative polymerase chain reaction, and gene expression microarrays. Results: Our results showed increased vascular inflammation, arterial wall thickness, and atherosclerosis in APPsw-Tg and ApoE-/-/APPsw-Tg mice. We further found that the expression of chitinase-3-like-1 (Chi3l1) is increased in the APPsw-Tg mouse artery and Chi3l1 mediates endothelial cell (EC) inflammation and vascular smooth muscle cell (VSMC) activation, which in turn exacerbates atherosclerosis. In addition, using two publicly available microarray datasets from the dorsolateral prefrontal cortex of people with AD and unaffected controls as well as inflamed human umbilical vein endothelial cells, we found that Chi3l1 and associated inflammatory gene were significantly associated with AD, evaluated by co-expression network analysis and functional annotation. Knockdown of Chi3l1 in the arterial endothelium in vivo suppressed the development of atherosclerosis. We also show that microRNA 342-3p (miR-342-3p) inhibits EC inflammation and VSMC activation through directly targeting Chi3l1, and that APPsw increased Chi3l1 expression by reducing miR-342-3p expression in the arterial endothelium, promoting atherosclerosis. Conclusion: Our findings suggest that targeting Chi3l1 might provide new diagnostic and therapeutic strategies for vascular diseases in patients with AD. © 2018, Ivyspring International Publisher.
DOI
10.7150/th20183
Appears in Collections:
약학대학 > 약학과 > Journal papers
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