Abstract
BackgroundCysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) 3 has been recently reported to play a role in regulating inflammation of vascular endothelial cells. However, the role of CCN3 in atherosclerosis, which is characterized by vascular inflammation, remains unclear.Hypothesis and ObjectivesOverexpression of CCN3 may relieve the inflammation response in and inhibit the progress of atherosclerosis. We aimed to explore the potential roles of CCN3 in inflammation in atherosclerosis.Strategy and Main ResultsIn in vitro studies using cultured human aortic endothelial cells and human umbilical vein endothelial cells, CCN3 mRNA and protein expression significantly decreased in response to tumor necrosis factor-α and interleukin-1β treatments (p<0.05), when analyzed by quantitative real-time polymerase chain reaction and Western blot. Using a mouse model of atherosclerosis, the mRNA and protein levels of CCN3 decreased by 72.2% (p = 0.041) and 86.4% (p = 0.036), respectively, compared with levels in wild-type control mice, respectively. Overexpression of CCN3 by adenovirus-mediated gene overexpression decreased low-density lipoprotein cholesterol by 48.9% (p = 0.017), total cholesterol by 58.9% (p = 0.031), and triglycerides by 56.8% (p = 0.022), and it increased high-density lipoprotein cholesterol level by 2.16-fold (p = 0.039), compared with control groups. Additionally, a reduced plaque area and increased fibrous cap were observed (p<0.05). Furthermore, CCN3 overexpression decreased cell adhesion molecule-1 mRNA expression by 84.7% (p = 0.007) and intercellular adhesion molecule-1 mRNA expression by 61.2% (p = 0.044). Inflammatory factors, including matrix metalloproteinases, cyclooxygenase 2, and tissue factor also significantly (p<0.05) decreased with CCN3 overexpression in the atherosclerotic mouse model. Additionally, CCN1 and CCN2, which have been reported to be highly expressed in aortic atherosclerotic plaques, were significantly downregulated (p<0.05) by CCN3 overexpression.ConclusionCCN3 overexpression is associated with control of inflammatory processes and reversion of dyslipidemia in the process of atherosclerosis, which implies that CCN3 may be a promising target in the treatment of atherosclerosis.
Highlights
Atherosclerosis is a worldwide disease that induces acute cardiocerebrovascular events, causing serious damage to human health [1]
CCN3 overexpression is associated with control of inflammatory processes and reversion of dyslipidemia in the process of atherosclerosis, which implies that CCN3 may be a promising target in the treatment of atherosclerosis
Similar results were obtained in human umbilical vein endothelial cells (HUVECs), where CCN3 mRNA expression was significantly decreased by 89.9% (p = 0.009) and 77.1% (p = 0.017) in response to tumor necrosis factor (TNF)-a and IL-1b treatments, respectively (Fig. 1B upper)
Summary
Atherosclerosis is a worldwide disease that induces acute cardiocerebrovascular events, causing serious damage to human health [1]. Six members of the family have been characterized, including cysteine-rich protein 61 (CCN1), connective tissue growth factor (CCN2), nephroblastoma overexpressed (CCN3), Wnt-inducible signaling pathway protein 1 (CCN4), Wnt-inducible signaling pathway protein 2 (CCN5), and Wnt-inducible signaling pathway protein 3 (CCN6) [4,5]. These proteins are proposed to be involved in diverse biological progresses. Cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed (CCN) 3 has been recently reported to play a role in regulating inflammation of vascular endothelial cells. CCN1 and CCN2, which have been reported to be highly expressed in aortic atherosclerotic plaques, were significantly downregulated (p,0.05) by CCN3 overexpression
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