Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury

Xia Lei, Debapriya Basu, Zhiqiang Li, Maoxiang Zhang, R. Dan Rudic, Xian Cheng Jiang, Weijun Jin

Research output: Contribution to journalArticle

Abstract

Objective: Atherosclerosis is a complex disease, involving elevated LDL-c, lipid accumulation in the blood vessel wall, foam cell formation and vascular dysfunction. Lowering plasma LDL-c is the cornerstone of current management of cardiovascular disease. However, new approaches which reduce plasma LDL-c and lessen the pathological vascular remodeling occurring in the disease should also have therapeutic value. Previously, we found that overexpression 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. Methods: Adenovirus mediated overexpression of hepatic profurin in Ldlr-/-mice and wild-type mice were used to evaluate effects of profurin on ApoB-containing lipoproteins, atherosclerosis and vascular remodeling. Results: Hepatic profurin overexpression resulted in a significant reduction in atherosclerotic lesion development in Ldlr-/-mice and a robust reduction in plasma LDL-c. Metabolic studies revealed lower secretion of ApoB and triglycerides in VLDL particles. 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. Profurin expression inhibited proliferation and migration in vascular smooth muscle cells in vitro. Conclusion: 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.

Original languageEnglish (US)
JournalAtherosclerosis
Volume236
Issue number1
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Furin
Apolipoproteins B
Atherosclerosis
Liver
Wounds and Injuries
Blood Vessels
Lipids
Lipoproteins
Proprotein Convertases
Foam Cells
Metabolome
Common Carotid Artery
Proteasome Endopeptidase Complex
Femoral Artery
Vascular Smooth Muscle
Adenoviridae
Smooth Muscle Myocytes
Ligation
Cardiovascular Diseases
Vascular Remodeling

Keywords

  • ApoB
  • Atherosclerosis
  • Furin
  • HDL
  • Prodomain
  • Typical proprotein convertase
  • Vascular remodeling
  • VLDL

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury. / Lei, Xia; Basu, Debapriya; Li, Zhiqiang; Zhang, Maoxiang; Rudic, R. Dan; Jiang, Xian Cheng; Jin, Weijun.

In: Atherosclerosis, Vol. 236, No. 1, 01.01.2014.

Research output: Contribution to journalArticle

Lei, Xia ; Basu, Debapriya ; Li, Zhiqiang ; Zhang, Maoxiang ; Rudic, R. Dan ; Jiang, Xian Cheng ; Jin, Weijun. / Hepatic overexpression of the prodomain of furin lessens progression of atherosclerosis and reduces vascular remodeling in response to injury. In: Atherosclerosis. 2014 ; Vol. 236, No. 1.
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AU - Basu, Debapriya

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AU - Zhang, Maoxiang

AU - Rudic, R. Dan

AU - Jiang, Xian Cheng

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