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

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.

Non‐alcoholic steatohepatitis aggravates nitric oxide synthase inhibition‐induced arteriosclerosis in SHRSP5/Dmcr rat model

“…The process for the oil red O staining of the mesenteric artery and aorta was based on previous reports . The mesenteric artery was carefully isolated from the intestine.…”

“…22 The process for the oil red O staining of the mesenteric artery and aorta was based on previous reports. 23,24 The mesenteric artery was carefully isolated from the intestine. The aorta and isolated mesenteric artery were fixed in 10% formalin for 10 minutes.…”

High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression

“…This discrepancy may be due to inter‐species differences, particularly in relation to the period of disease development. In addition, we have recently found that the loss of ADAMTS4 resulted in the attenuation of both atherosclerotic plaque formation and the plaque stability . Our results suggest that HA tended to suppress the mRNA expression of more than one ADAMTS, implying that aggrecanase activity can be controlled by HA.…”

Metalloproteinases in atherosclerosis

“…Moreover, elevated circulating levels of ADAMTS4 have been reported in patients with coronary artery disease and acute coronary syndromes (Zha et al 2010). Concurring, loss of ADAMTS4 reduced atherosclerosis and enhanced plaque stability in Apoe KO mice (Kumar et al 2016). A protective role in atherosclerosis has been ascribed to ADAMTS5 as its expression is depleted in atherosclerotic aortas, leading to the accumulation of proteoglycans such as versican and biglycan, which may favour lipid retention and macrophage accumulation (Didangelos et al 2012).…”