Document Detail


Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening.
MedLine Citation:
PMID:  23103162     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE-containing high-density lipoprotein (apoE-HDL) maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop that increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE null mice. This stiffening can be reduced by administration of the lysyl oxidase inhibitor BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics and that this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol.
Authors:
Devashish Kothapalli; Shu-Lin Liu; Yong Ho Bae; James Monslow; Tina Xu; Elizabeth A Hawthorne; Fitzroy J Byfield; Paola Castagnino; Shilpa Rao; Daniel J Rader; Ellen Puré; Michael C Phillips; Sissel Lund-Katz; Paul A Janmey; Richard K Assoian
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-10-25
Journal Detail:
Title:  Cell reports     Volume:  2     ISSN:  2211-1247     ISO Abbreviation:  Cell Rep     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-05-09     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101573691     Medline TA:  Cell Rep     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1259-71     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.
Affiliation:
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE40637
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MeSH Terms
Descriptor/Qualifier:
Aminopropionitrile / pharmacology,  therapeutic use
Animals
Aorta / drug effects,  metabolism
Apolipoprotein E3 / pharmacology
Apolipoproteins E / deficiency,  genetics,  metabolism*
Atherosclerosis / drug therapy,  metabolism,  pathology
Cells, Cultured
Cholesterol, HDL / pharmacology*
Collagen Type I / metabolism
Cyclooxygenase 2 / metabolism
Extracellular Matrix / genetics,  metabolism*
Extracellular Matrix Proteins / genetics,  metabolism
Fibronectins / metabolism
Gene Expression
Humans
Macrophages / drug effects,  metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
MicroRNAs / metabolism
Protein-Lysine 6-Oxidase / antagonists & inhibitors,  genetics,  metabolism
Vascular Stiffness / drug effects
Grant Support
ID/Acronym/Agency:
HL093283/HL/NHLBI NIH HHS; HL22633/HL/NHLBI NIH HHS; HL56083/HL/NHLBI NIH HHS; HL66250/HL/NHLBI NIH HHS; P01 HL022633/HL/NHLBI NIH HHS; P01 HL062250/HL/NHLBI NIH HHS; R01 HL056083/HL/NHLBI NIH HHS; R01 HL093283/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Apolipoprotein E3; 0/Apolipoproteins E; 0/Cholesterol, HDL; 0/Collagen Type I; 0/Extracellular Matrix Proteins; 0/Fibronectins; 0/MIRN145 microRNA, mouse; 0/MicroRNAs; 149137-54-2/Lox protein, mouse; 151-18-8/Aminopropionitrile; EC 1.14.99.1/Cyclooxygenase 2; EC 1.4.3.13/Protein-Lysine 6-Oxidase
Comments/Corrections

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