Moe Kyaw Thu, Naylynn Tin Maung, Yin Nwe Oo, Khairunnisa Katwadi, Allen John C, Wong Meng Cheong, Chin-Dusting Jaye, Wong Philip
Research and Development Unit, National Heart Centre Singapore, Singapore.
J Vasc Res. 2013;50(3):228-37. doi: 10.1159/000350542. Epub 2013 May 22.
BACKGROUND/AIMS: Neointimal thickening results from inflammation in association with vascular smooth muscle cell (VSMC) proliferation. We studied the role of perivascular adipose tissue (PVAT) on VSMC proliferation and intima-media thickening (IMT) in a rodent model of chronic inflammation.
The abdominal aorta and surrounding PVAT of tumour necrosis factor (TNF)-α-injected mice were examined 28 days after administration. Plasma and PVAT cytokines were measured with Milliplex™ assays. Inflammatory cells were examined with immunofluorescence. Expression of transforming growth factor (TGF)-β1, matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 was examined with immunohistochemistry, immunoblotting and zymography. IMT was determined. Cell proliferation and TGF-β1 mRNA levels were examined after treating VSMC with PVAT homogenates ± MMP-2 inhibitors (batimastat, ARP 100 or TIMP-2) and SB-431542, a selective inhibitor of the TGF-β-type 1 receptor.
Significant increases in CD3, CD68, neutrophils, vascular cell adhesion molecule-1 and MMP-2 in PVAT, and TGF-β1 and IMT of the aorta of TNF-α-injected mice were observed. PVAT of TNF-α-injected mice significantly up-regulated TGF-β1 and increased cell proliferation in a dose-dependent manner and was attenuated by SB-431542, batimastat, ARP 100 and TIMP-2.
Our study shows that chronic PVAT inflammation leads to MMP-mediated increase in TGF-β1 and hence VSMC proliferation.
背景/目的：新生内膜增厚是由炎症与血管平滑肌细胞（VSMC）增殖共同引起的。我们在慢性炎症的啮齿动物模型中研究了血管周围脂肪组织（PVAT）对VSMC增殖和内膜中层增厚（IMT）的作用。
在给予肿瘤坏死因子（TNF）-α后28天，检查注射TNF-α小鼠的腹主动脉及周围PVAT。用Milliplex™检测法测量血浆和PVAT细胞因子。用免疫荧光法检查炎症细胞。用免疫组织化学、免疫印迹和酶谱法检测转化生长因子（TGF）-β1、基质金属蛋白酶（MMP）-2、MMP-9和MMP-12的表达。测定IMT。在用PVAT匀浆±MMP-2抑制剂（batimastat、ARP 100或TIMP-2）以及TGF-β1型受体选择性抑制剂SB-431542处理VSMC后，检测细胞增殖和TGF-β1 mRNA水平。
观察到注射TNF-α小鼠的PVAT中CD3、CD68、中性粒细胞、血管细胞黏附分子-1和MMP-2显著增加，且主动脉的TGF-β1和IMT也增加。注射TNF-α小鼠的PVAT显著上调TGF-β1并以剂量依赖方式增加细胞增殖，而SB-431542、batimastat、ARP 100和TIMP-2可使其减弱。
我们的研究表明，慢性PVAT炎症导致MMP介导的TGF-β1增加，进而引起VSMC增殖。
