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

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.

Chitinase-3 like-protein-1 function and its role in diseases

“…Conversely, no relationship is found between CHI3L1 overexpression and survival in patients with cervical squamous cell carcinoma and liver cancer, while a negative correlation was observed between among patients bearing sarcoma. (from https://kmplot.com, http://www.cgga.org.cn) [177][178][179][180] Serum CHI3L1↑ → liver fibrosis Alcoholic liver disease 181,182 CHI3L1↑ → liver fibrosis Non-alcoholic fatty liver disease 183 CHI3L1↑ → liver fibrosis Bowel diseases IBD Fecal CHI3L1 → mucosal inflammation 184 and endoscopic activity 185 Colitis CHI3L1 binds to bacterial chitin-binding protein, 186,187 enhances bacterial adhesion and invasion, 60 activates Akt signaling 145 and IL-6-mediated STAT3 Phosphorylation 188 Cardiovascular Atherosclerosis CHI3L1↑ → coronary 189,190 and carotid 191 atherosclerosis severity↑, risk↑, 193 exacerbates atherosclerosis 192 Coronary artery disease Type 1 194 and type 2 195 diabetes CHI3L1↑…”

“…Moreover, atherosclerosis is exacerbated by CHI3L1 in amyloid precursor protein transgenic mice. 192 Accordingly, CHI3L1 gene silencing could downregulate the expression of local proinflammatory mediators and inhibit plaques progression. 193 Additionally, CHI3L1 is an early inflammatory marker in diabetic subjects even in the presence of a low atherosclerotic background, 194,195 and is elevated in patients with peripheral arterial disease and diabetes or pre-diabetes.…”

Chitinase 3 like 1 suppresses the stability and activity of p53 to promote lung tumorigenesis

“…Chitinase 3-like-1 (Chi3L1), also called a breast regression protein 39 (BRP-39) in mouse and YKL-40 in human, is known as a secreted glycoprotein and prototypic mammalian chitinase like protein [11,12]. Increased expression of Chi3L1 protein and mRNA have been shown in various disease models and states including rheumatoid arthritis schizophrenics, inflammatory bowel disease, chronic obstructive pulmonary disease, asthma, diabetes, and atherosclerosis [13][14][15][16][17][18][19], Especially, Chi3L1 expression has been found in a variety of cancer cells such as breast, lung, prostate, colon, rectum, ovary, kidney, breast, glioblastomas, and malignant melanoma [20][21][22][23][24][25][26].…”

The Role of miR-342 in Vascular Health. Study in Subclinical Cardiovascular Disease in Mononuclear Cells, Plasma, Inflammatory Cytokines and PANX2

“…Out of 2000 miRNAs that have been discovered in humans, miR-342-3p/-5p appear to have great potential to repress inflammation in atherosclerosis [ 15 , 16 ]. Additionally, current studies have shown miR-342-3p l to increase the cell survival, motility and proliferation of osteoclast precursors [ 17 ].…”