Gene silencing of TACE enhances plaque stability and improves vascular remodeling in a rabbit model of atherosclerosis.

Xueqiang Zhao,Peili Bu,Yun Zhang,Xuping Wang,Yuxia Zhao,Jing Kong,Cheng Zhang

doi:10.1038/srep17939

Abstract

We aimed to test the hypothesis that gene silencing of tumor necrosis factor alpha converting enzyme (TACE) may attenuate lesion inflammation and positive vascular remodeling and enhance plaque stability in a rabbit model of atherosclerosis. Lentivirus-mediated TACE shRNA was injected into the abdominal aortic plaques of rabbits which effectively down-regulated TACE expression and activities from week 8 to week 16. TACE gene silencing reduced remodeling index and plaque burden, and diminished the content of macrophages and lipids while increased that of smooth muscle cells and collagen in the aortic plaques. In addition, TACE gene silencing attenuated the local expression of P65, iNOS, ICAM-1, VEGF and Flt-1 and activities of MMP9 and MMP2 while increased the local expression of TGF-β1 together with reduced number of neovessels in the aorta. TACE shRNA treatment resulted in down-regulated expression of TACE in macrophages and blunted ERK-P38 phosphorylation and tube formation of co-cultured mouse vascular smooth muscle cells or human umbilical vein endothelial cells. In conclusion, gene silencing of TACE enhanced plaque stability and improved vascular positive remodeling. The mechanisms may involve attenuated local inflammation, neovascularization and MMP activation, as well as enhanced collagen production probably via down-regulated ERK-NF-κB and up-regulated TGF-β1 signaling pathways.

Highlights

Pathological studies have demonstrated that in the majority of patients with acute coronary syndromes, the culprit lesions are caused by intraluminal thrombosis secondary to rupture of vulnerable plaques, which are characterized by thinning of the fibrous cap, scarcity of collagen and smooth muscle cells, abundance of macrophages and activated T cells, and intraplaque neovascularization[10,11]
Tumor necrosis factor alpha converting enzyme (TACE) expression level was positively correlated with neovessel number (Fig. 1J) and macrophage content in plaques (Fig. 1I)
We firstly reported that endogenous TACE was highly expressed in unstable plaques and gene silencing of TACE enhanced plaque stability and improved vascular positive remodeling

Summary

Introduction

Pathological studies have demonstrated that in the majority of patients with acute coronary syndromes, the culprit lesions are caused by intraluminal thrombosis secondary to rupture of vulnerable plaques, which are characterized by thinning of the fibrous cap, scarcity of collagen and smooth muscle cells, abundance of macrophages and activated T cells, and intraplaque neovascularization[10,11]. A variety of mechanisms have been proposed, overwhelming evidence suggests that local inflammation plays a major role in initiating the cascade of plaque instability[12]. Macrophages abundant in vulnerable plaque excrete a variety of cytokines and matrix-metalloproteinases (MMPs), which may impede the synthesis or accelerate the degradation of collagen in the fibrous cap, leading to so called thin-cap fibroatheroma. The effect of TACE on collagen production and degradation in atherosclerotic plaques is still unknown. A series of in vivo and in vitro experiments were designed and performed to test this hypothesis and the possible mechanisms underlying these effects were investigated

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Conclusion