Increased Expression of Chitinase 3-Like 1 in Aorta of Patients with Atherosclerosis and Suppression of Atherosclerosis in Apolipoprotein E-Knockout Mice by Chitinase 3-Like 1 Gene Silencing

Mediators of Inflammation, Mar 2014

Introduction. The purpose of this study was to investigate the changes of chitinase 3-like 1 (CHI3L1) in the aorta of patients with coronary atherosclerosis and to determine whether inhibition of CHI3L1 by lentivirus-mediated RNA interference could stabilize atherosclerotic plaques in apolipoprotein E-knockout (ApoE−/−) mice. Methods. We collected discarded aortic specimens from patients undergoing coronary artery bypass graft surgery and renal arterial tissues from kidney donors. A lentivirus carrying small interfering RNA targeting the expression of CHI3L1 was constructed. Fifty ApoE−/− mice were divided into control group and CHI3L1 gene silenced group. A constrictive collar was placed around carotid artery to induce plaques formation. Then lentivirus was transfected into carotid plaques. Results. We found that CHI3L1 was overexpressed in aorta of patients with atherosclerosis and its expression was correlated with the atherosclerotic risk factors. After lentivirus transduction, mRNA and protein expression of CHI3L1 were attenuated in carotid plaques, leading to reduced plaque content of lipids and macrophages, and increased plaque content of collagen and smooth muscle cells. Moreover, CHI3L1 gene silencing downregulated the expression of local proinflammatory mediators. Conclusions. CHI3L1 is overexpressed in aorta from patients with atherosclerosis and the lentivirus-mediated CHI3L1 gene silencing could represent a new strategy to inhibit plaques progression.

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Increased Expression of Chitinase 3-Like 1 in Aorta of Patients with Atherosclerosis and Suppression of Atherosclerosis in Apolipoprotein E-Knockout Mice by Chitinase 3-Like 1 Gene Silencing

Increased Expression of Chitinase 3-Like 1 in Aorta of Patients with Atherosclerosis and Suppression of Atherosclerosis in Apolipoprotein E-Knockout Mice by Chitinase 3-Like 1 Gene Silencing Zushun Gong,1 Shanshan Xing,2 Fei Zheng,1 and Qichong Xing1 1Department of Cardiology, Qianfoshan Hospital, Shandong University, 16766 Jingshi Road, Jinan 250014, China 2Department of Cardiology, Shandong University of Traditional Chinese Medicine, Jinan 250355, China Received 2 July 2013; Revised 27 November 2013; Accepted 23 January 2014; Published 4 March 2014 Academic Editor: Claudia Monaco Copyright © 2014 Zushun Gong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Introduction. The purpose of this study was to investigate the changes of chitinase 3-like 1 (CHI3L1) in the aorta of patients with coronary atherosclerosis and to determine whether inhibition of CHI3L1 by lentivirus-mediated RNA interference could stabilize atherosclerotic plaques in apolipoprotein E-knockout (ApoE−/−) mice. Methods. We collected discarded aortic specimens from patients undergoing coronary artery bypass graft surgery and renal arterial tissues from kidney donors. A lentivirus carrying small interfering RNA targeting the expression of CHI3L1 was constructed. Fifty ApoE−/− mice were divided into control group and CHI3L1 gene silenced group. A constrictive collar was placed around carotid artery to induce plaques formation. Then lentivirus was transfected into carotid plaques. Results. We found that CHI3L1 was overexpressed in aorta of patients with atherosclerosis and its expression was correlated with the atherosclerotic risk factors. After lentivirus transduction, mRNA and protein expression of CHI3L1 were attenuated in carotid plaques, leading to reduced plaque content of lipids and macrophages, and increased plaque content of collagen and smooth muscle cells. Moreover, CHI3L1 gene silencing downregulated the expression of local proinflammatory mediators. Conclusions. CHI3L1 is overexpressed in aorta from patients with atherosclerosis and the lentivirus-mediated CHI3L1 gene silencing could represent a new strategy to inhibit plaques progression. 1. Introduction Coronary artery disease (CAD) has become the principal cause of death in the world. As a systematic disease which usually affects large- and medium-sized elastic and muscular arteries all over the body, atherosclerosis is the underlying pathology of most CADs. Substantial evidence supports the concept that atherosclerosis is a chronic inflammatory disease characterized by the deposition of fibrous matrix and lipids in the arterial wall. According to the “response-to-injury” hypothesis, the endothelial denudation and endothelial dysfunction caused by some risk factors are the first step in the development of atherosclerosis [1]. The activated endothelial cells facilitate monocytes infiltration into the vessel wall. Then, these monocytes differentiate into macrophages, which accumulate lipids from the circulation and remain in the vessel wall, thereby becoming foam cells. These cells mentioned above can synthesize and release proinflammatory molecules such as tumor necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin 1 (IL-1), which can induce further accumulation of monocytes and migration and proliferation of vascular smooth muscle cells (SMCs) [2]. Chitinase 3-like 1 (CHI3L1), also called cartilage glycoprotein 39 or YKL-40 in human and breast regression protein 39 in mice, is a 40 kDa chitin-binding glycoprotein without chitinase activity, and it has been shown to act as an important regulator of acute and chronic inflammation [3, 4]. It is secreted by a variety of cells, including SMCs and macrophages and is found in tissues with inflammation and extracellular tissue remodeling. Up to now, several studies have shown an important link between CHI3L1 and inflammation or metabolic diseases, including asthma [5], hypertension [6], diabetes mellitus [7, 8], insulin resistance [9], and atherosclerosis [10, 11], and naturally believe that CHI3L1 may be a potential biomarker and therapeutic target for the related diseases. Although the relationship between CHI3L1 and CAD is important, there is a controversy in the association between blood CHI3L1 levels and the severity of atherosclerosis. One study investigating the role of CHI3L1 in patients with peripheral arterial disease showed that severity of atherosclerosis is associated with higher blood CHI3L1 levels [12], and another paper concluded that circulating CHI3L1 was not specifically related to the size of atherosclerotic stenosis [13]. These conflicting results may be due to the differences in the study participants and diagnostic modality for evaluation of coronary artery and severity of atherosclerosis. (...truncated)


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Zushun Gong, Shanshan Xing, Fei Zheng, Qichong Xing. Increased Expression of Chitinase 3-Like 1 in Aorta of Patients with Atherosclerosis and Suppression of Atherosclerosis in Apolipoprotein E-Knockout Mice by Chitinase 3-Like 1 Gene Silencing, Mediators of Inflammation, 2014, 2014, DOI: 10.1155/2014/905463