Gax gene transfer inhibits vascular remodeling induced by adventitial inflammation in rabbits
Introduction
It has been recognized that excessive proliferation of adventitial cells in response to vessel wall injury contributes to vascular remodeling or restenosis that occurs in 30–50% of patients after angioplasty [1]. Almost three-quarters (73%) of the late lumen loss are due to a decrease in external elastic membrane area and only 27% are due to an increase in intimal and medial thickness [1]. Accumulative evidence indicates that vascular remodeling is closely associated with adventitial inflammation [2], [3] as local inflammatory response may result in increased cytokine/growth factor production that in turn promotes adventitial cell proliferation and migration. Our recent work revealed that cross-talk among Smad, MAPK and integrin signaling pathways were essential in regulating adventitial fibroblast function and vascular remodeling [4], although the exact mechanisms by which inflammation induces vascular remodeling remain to be elucidated.
Homeobox genes encode transcription factors and with a highly conserved DNA-binding domain regulate cell growth, differentiation and migration [5], [6]. Among nuclear transcription inhibitors, growth arrest-specific homeobox (Gax) is a unique homeobox gene and acts as a negative regulator of mesodermal tissue proliferation [7], [8]. Gax is mainly expressed in adult cardiovascular tissues and exerts remarkable inhibitory effects on proliferation of vascular endothelial and smooth muscle cells in vitro and in vivo[6], [9], [10]. Recent study in our laboratory demonstrated a significant inhibitory effect of Gax gene transfer on adventitial fibroblast bioactivities in vitro[4]. However, whether Gax can effectively inhibit adventitial cell bioactivities and vascular remodeling in vivo is still unknown. Therefore, the present study was undertaken to test the hypothesis that adenovirus-mediated Gax gene transfer may effectively inhibit vascular remodeling via interrupting the cross-talk among multiple signaling pathways regulating adventitial cell bioactivities in a rabbit model of adventitial inflammation-induced vascular remodeling.
Section snippets
Materials and methods
Detailed materials and methods are described in the Supplementary data.
Biochemical measurements in vivo
During the experiment in vivo, three rabbits died of anesthetic accident, vessel rupture or intestine rupture and the remaining 47 rabbits (10 rabbits in the normal control group and 37 in the experimental group) completed the study.
In comparison with the normal control group, serum levels of CRP, TGF-β1, IL-1β, IL-6, IL-8, MCP-1, TNF-α, VCAM-1 and ICAM-1 were significantly increased in the model control, saline-treated and Ad-GFP-treated groups (all P < 0.01, Supplementary Table II). The
Discussion
The major finding of the present study was that by applying a peri-aortic collar and local injection of LPS in rabbits, an animal model of vascular remodeling induced by adventitial inflammation can be established, and adenovirus-mediated Gax gene transfer may effectively inhibit vascular remodeling via interrupting the cross-talk among multiple signaling pathways regulating adventitial cell bioactivities in these rabbits. To the best of our knowledge, this is the first study to report the
Disclosure
None declared.
Acknowledgments
We thank Prof. Wei Cheng Hu at Shandong University, China and Prof. Qingbo Xu at St. George's, University of London, UK for their excellent advice. This study was supported by the National 973 Basic Research Program of China (No. 2009CB521900), the National High-tech Research and Development Program of China (No. 2006AA02A406), the Program of Introducing Talents of Discipline to Universities (No. B07035), the State Key Program of National Natural Science of China (No. 60831003) and grants from
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These authors contributed to this work equally.