Theranostics 2018; 8(3):749-766. doi:10.7150/thno.20183 This issue Cite

Research Paper

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

Yu Yeon Jung1,2*, Ki Cheon Kim1*, Mi Hee Park1*, Youngsik Seo3, Heonyong Park3, Min Hee Park4,5, Jun Chang4, Dae Youn Hwang6, Sang Bae Han1, Sanghyeon Kim7, Dong Ju Son1,5*✉, Jin Tae Hong1✉

1. College of Pharmacy & Medical Research Center, Chungbuk National University, Cheongju, Chungbuk 28160, Korea;
2. Department of Dental Hygiene, Gwangyang Health Sciences University, Gwangyang, Jeonnam 57764, Korea;
3. Department of Molecular Biology and Institute of Nanosensor Biotechnology, Dankook University, Yongin, Gyeonggi 16890, Korea;
4. Division of Life & Pharmaceutical Sciences, and the Center for Cell Signaling & Drug Discovery Research, Ewha Womans University, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, Korea;
5. Life Science Research Center, NovaKmed Co. Ltd., 1646 Yuseong-daero, Yuseong-gu, Daejeon 34054, Korea;
6. College of Biomaterials Science, Pusan National University, Miryang, Kyungnam 50463, Korea;
7. Stanley Brain Research Laboratory, Stanley Medical Research Institute, 9800 Medical Center Drive, Rockville, MD 20850, USA.
* These authors contributed equally to this work.

Citation:
Jung YY, Kim KC, Park MH, Seo Y, Park H, Park MH, Chang J, Hwang DY, Han SB, Kim S, Son DJ, Hong JT. Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice. Theranostics 2018; 8(3):749-766. doi:10.7150/thno.20183. https://www.thno.org/v08p0749.htm
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Abstract

Graphic 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.

Keywords: Alzheimer's diseases, amyloid precursor protein, atherosclerosis, chitinase-3-like-1, endothelial cells, microRNA 342-3p.


Citation styles

APA
Jung, Y.Y., Kim, K.C., Park, M.H., Seo, Y., Park, H., Park, M.H., Chang, J., Hwang, D.Y., Han, S.B., Kim, S., Son, D.J., Hong, J.T. (2018). Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice. Theranostics, 8(3), 749-766. https://doi.org/10.7150/thno.20183.

ACS
Jung, Y.Y.; Kim, K.C.; Park, M.H.; Seo, Y.; Park, H.; Park, M.H.; Chang, J.; Hwang, D.Y.; Han, S.B.; Kim, S.; Son, D.J.; Hong, J.T. Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice. Theranostics 2018, 8 (3), 749-766. DOI: 10.7150/thno.20183.

NLM
Jung YY, Kim KC, Park MH, Seo Y, Park H, Park MH, Chang J, Hwang DY, Han SB, Kim S, Son DJ, Hong JT. Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice. Theranostics 2018; 8(3):749-766. doi:10.7150/thno.20183. https://www.thno.org/v08p0749.htm

CSE
Jung YY, Kim KC, Park MH, Seo Y, Park H, Park MH, Chang J, Hwang DY, Han SB, Kim S, Son DJ, Hong JT. 2018. Atherosclerosis is exacerbated by chitinase-3-like-1 in amyloid precursor protein transgenic mice. Theranostics. 8(3):749-766.

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