Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening.

Cell Rep 2012 Nov 25;2(5):1259-71. Epub 2012 Oct 25.

Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA.

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.

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S22111247120032
Publisher Site
http://dx.doi.org/10.1016/j.celrep.2012.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535179PMC
November 2012
11 Reads

Publication Analysis

Top Keywords

lysyl oxidase
8
apoe apoe-containing
8
arterial stiffening
8
cardiovascular disease
8
apoe
6
arterial
5
loop increases
4
increases expression
4
mice stiffening
4
elevated cholesterol
4
feed-forward loop
4
expression collagen-i
4
highly elevated
4
atherosclerosis despite
4
fibronectin lysyl
4
despite highly
4
collagen-i fibronectin
4
cholesterol macrophage
4
driven feed-forward
4
apoe interrupts
4

Similar Publications