TY - JOUR
T1 - Tumor necrosis factor-α induces aortic intima-media thickening via perivascular adipose tissue inflammation
AU - Moe, Kyaw Thu
AU - Naylynn, Tin Maung
AU - Yin, Nwe Oo
AU - Khairunnisa, Katwadi
AU - Allen, John C.
AU - Wong, Meng Cheong
AU - Chin-Dusting, Jaye
AU - Wong, Philip
PY - 2013/7
Y1 - 2013/7
N2 - 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. Methods: 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. Results: 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. Conclusions: Our study shows that chronic PVAT inflammation leads to MMP-mediated increase in TGF-β1 and hence VSMC proliferation.
AB - 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. Methods: 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. Results: 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. Conclusions: Our study shows that chronic PVAT inflammation leads to MMP-mediated increase in TGF-β1 and hence VSMC proliferation.
KW - Chronic inflammation
KW - Matrix metalloproteinase-2
KW - Perivascular adipose tissue
KW - Tumor necrosis factor-α
KW - Vascular smooth muscle cells
UR - http://www.scopus.com/inward/record.url?scp=84878070634&partnerID=8YFLogxK
U2 - 10.1159/000350542
DO - 10.1159/000350542
M3 - Article
C2 - 23711955
AN - SCOPUS:84878070634
SN - 1018-1172
VL - 50
SP - 228
EP - 237
JO - Journal of Vascular Research
JF - Journal of Vascular Research
IS - 3
ER -