title: Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening.
abstract: 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.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.
authors.forename: Devashish
authors.initials: D
authors.lastname: Kothapalli
authors.forename: Shu-Lin
authors.initials: SL
authors.lastname: Liu
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Bae
authors.forename: James
authors.initials: J
authors.lastname: Monslow
authors.forename: Tina
authors.initials: T
authors.lastname: Xu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hawthorne
authors.forename: Fitzroy J
authors.initials: FJ
authors.lastname: Byfield
authors.forename: Paola
authors.initials: P
authors.lastname: Castagnino
authors.forename: Shilpa
authors.initials: S
authors.lastname: Rao
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Michael C
authors.initials: MC
authors.lastname: Phillips
authors.forename: Sissel
authors.initials: S
authors.lastname: Lund-Katz
authors.forename: Paul A
authors.initials: PA
authors.lastname: Janmey
authors.forename: Richard K
authors.initials: RK
authors.lastname: Assoian
mesh_terms: D000629:Aminopropionitrile / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D053318:Apolipoprotein E3 / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059289:Vascular Stiffness / Q000187:drug effects
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C077112:Lox protein, mouse; D000629:Aminopropionitrile; D051546:Cyclooxygenase 2; D008249:Protein-Lysine 6-Oxidase