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

Yu Yeon Jung, Ki Cheon Kim, Mi Hee Park, Youngsik Seo, Heonyong Park, Min Hee Park, Jun Chang, Dae Youn Hwang, Sang Bae Han, Sanghyeon Kim, Dong Ju Son, Jin Tae Hong

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish
Pages (from-to)749-766
Number of pages18
JournalTheranostics
Volume8
Issue number3
DOIs
StatePublished - 2018

Keywords

  • Alzheimer's diseases
  • Amyloid precursor protein
  • Atherosclerosis
  • Chitinase-3-like-1
  • Endothelial cells
  • microRNA 342-3p

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