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. 2016 Aug 5:6:31130.
doi: 10.1038/srep31130.

Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice

Saran Kumar  1 , Mo Chen  1 , Yan Li  1 , Fiona H S Wong  2 , Chung Wee Thiam  2 , Md Zakir Hossain  3 , Kian Keong Poh  4   5 , Satoshi Hirohata  6 , Hiroko Ogawa  7 , Véronique Angeli  2 , Ruowen Ge  1
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Loss of ADAMTS4 reduces high fat diet-induced atherosclerosis and enhances plaque stability in ApoE(-/-) mice

Saran Kumar et al. Sci Rep. .

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by formation of lipid-rich plaques on the inner walls of arteries. ADAMTS4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase that regulates versican turnover in the arterial wall and atherosclerotic plaques. Recent reports indicated elevated ADAMTS4 level in human atherosclerotic plaques and in the plasma of acute coronary syndrome patients. Nevertheless, whether increased ADAMTS4 is a consequence of atherosclerosis or ADAMTS4 has a causal role in atherogenesis remains unknown. In this work, we investigated the role of ADAMTS4 in diet induced atherosclerosis using apolipoprotein E deficient (ApoE(-/-)) and Adamts4 knockout mice. We show that ADAMTS4 expression increases in plaques as atherosclerosis progresses in ApoE(-/-) mice. ApoE(-/-)Adamts4(-/-) double knockout mice presented a significant reduction in plaque burden at 18 weeks of age. Loss of ADAMTS4 lead to a more stable plaque phenotype with a significantly reduced plaque vulnerability index characterized by reduced lipid content and macrophages accompanied with a significant increase in smooth muscle cells, collagen deposition and fibrotic cap thickness. The reduced atherosclerosis is accompanied by an altered plasma inflammatory cytokine profile. These results demonstrate for the first time that ADAMTS4 contributes to diet induced atherosclerosis in ApoE(-/-) mice.

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Figures

Figure 1
Figure 1. Comparison of atherosclerosis in 12-weeks old ApoE−/− and ApoE−/−Adams4−/− mice.
(a) Photos of the aortic arch in wildtype, ApoE−/− and ApoE−/−Adams4−/− mice. Arrowhead indicates the brachiocephalic artery region with prominent lesion. (b) en face ORO stained main aortic tree (from the ascending aorta to the iliac bifurcation devoid of any branches) of 12-weeks old mice. (c) Quantification of the ORO positive area represented as percentage of total arterial trunk area (n = 8 for all ApoE−/− and ApoE−/−Adams4−/− mice, n = 4 for C57BL/6J male control mice). Values shown are mean ± SEM.
Figure 2
Figure 2. Reduced atherosclerotic lesions in 18-weeks old ApoE−/−Adamts4−/− mice.
(a) Photos of the aortic arch. Dotted circle indicates the aortic arch region with prominent lesion. (b) en face ORO stained main trunk of the aortic tree of 18-week old mice. (c) Quantification of the ORO positive area of the en face images shown in panel b (n = 8 for all ApoE−/− and ApoE−/−Adams4−/− mice, n = 4 for C57BL/6J male control mice).
Figure 3
Figure 3. Lesion morphology of the brachiocephalic artery in 12-weeks old mice.
(a) Representative images of 7 μm sections of brachiocephalic artery stained for ORO, CD68, SMA and collagen. (b) Quantification of the staining represented as a percentage of stained area over the complete plaque area (n = 5 mice, with 5 sections from each brachiocephalic trunk). Values shown are mean ± SEM.
Figure 4
Figure 4. Brachiocephalic artery plaque assessment in 18-weeks old mice.
(a) Representative images of brachiocephalic artery stained for ORO, CD68, SMA and collagen. (b) Quantification of the staining represented as a percentage of stained area over the complete plaque area (n = 5 mice, with 5 sections from each brachiocephalic trunk). Values shown are mean ± SEM.
Figure 5
Figure 5. Elevated levels of ADAMTS4 in plaques and plasma of ApoE−/− mice as atherosclerosis progresses.
(a) ADAMTS4 expression in the plaques of 12 and 18 weeks old ApoE−/− mice. (b) Quantification of the ADAMTS4 positive stained area expressed as percentage of total lesion area (n = 5 mice, with 5 sections from each brachiocephalic artery). (c) Plasma ADAMTS4 level in ApoE-null mice (n = 8). Values shown are mean ± SEM.
Figure 6
Figure 6. Cells expressing ADAMTS4 in the plaque.
Co-localization of ADAMTS4 with CD68 (a) and SMA (b) in brachiocephalic aortic plaques of 18 weeks old ApoE−/− mice.
Figure 7
Figure 7. Plasma cytokine profile change in ApoE−/−Adams4−/− mice.
Comparison of cytokines in the plasma from 18 weeks old mice (n = 3, each sample is a pool of blood plasma from 4 mice). Values shown are mean ± SEM.
Figure 8
Figure 8. Versican degradation in ApoE−/−Adams4−/− mice.
(a) Representative image of the brachiocephalic artery section stained with versican neoepitope antibody. (b) Quantification of degraded versican (n = 5, 5 sections per brachiocephalic trunk).
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