Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.
Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury.
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DOI：
10.1016/j.atherosclerosis.2014.06.015
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发表时间：
2014-09
期刊：
影响因子：
5.3
通讯作者：
Jin W
中科院分区：
文献类型：
--
作者：
Lei X;Basu D;Li Z;Zhang M;Rudic RD;Jiang XC;Jin W
Atherosclerosis is a complex disease, involving elevated LDL-c levels, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c levels is the cornerstone of current management of cardiovascular disease. However, new approaches that can reduce plasma LDL-c levels and lessen the pathological vascular remodeling that occurs in the disease should also have therapeutic value. Previously, we found that over-expression of profurin, the 83-amino acid prodomain of the proprotein convertase furin, lowered plasma HDL levels in wild-type mice. The question that remained was whether it had effects on apolipoprotein B (ApoB)-containing lipoproteins. In this study, we evaluated profurin for effects on ApoB-containing lipoproteins, atherosclerosis and vascular remodeling in vivo. Hepatic profurin overexpression resulted in a significant reduction in atherosclerotic lesion development in Ldlr−/− mice and a robust reduction in plasma LDL-c levels. Metabolic studies revealed that the secretion of ApoB and triglycerides in VLDL particles was greatly reduced. Mechanistic studies showed that in the presence of profurin, hepatic ApoB, mainly ApoB100, was degraded by proteasomes. There was no effect on ApoB mRNA expression. Importantly, short-term hepatic profurin overexpression did not result in hepatic lipid accumulation. Blood vessel wall thickening caused by either wire-induced femoral artery injury or common carotid artery ligation was reduced. When expressed in vascular smooth muscle cells in vitro, profurin inhibited proliferation and migration. These results indicate that a profurin-based therapy has the potential to treat atherosclerosis by improving metabolic lipid profiles and reducing both atherosclerotic lesion development and pathological vascular remodeling.
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