Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.

Björkegren, Johan L M ; Hägg, Sara ; Talukdar, Husain A ; Foroughi Asl, Hassan ; Jain, Rajeev K ; Cedergren, Cecilia ; Shang, Ming-Mei ; Rossignoli, Aránzazu ; Takolander, Rabbe and Melander, Olle LU orcid , et al. (2014) In PLoS Genetics 10(2).
Abstract
Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with... (More)
Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Genetics
volume
10
issue
2
article number
e1004201
publisher
Public Library of Science (PLoS)
external identifiers
  • pmid:24586211
  • wos:000332021500024
  • scopus:84901731028
  • pmid:24586211
ISSN
1553-7404
DOI
10.1371/journal.pgen.1004201
language
English
LU publication?
yes
id
44587cde-fd9e-41de-b344-c9bdb5119595 (old id 4384182)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24586211?dopt=Abstract
date added to LUP
2016-04-01 11:00:55
date last changed
2024-01-07 06:27:43
@article{44587cde-fd9e-41de-b344-c9bdb5119595,
  abstract     = {{Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.}},
  author       = {{Björkegren, Johan L M and Hägg, Sara and Talukdar, Husain A and Foroughi Asl, Hassan and Jain, Rajeev K and Cedergren, Cecilia and Shang, Ming-Mei and Rossignoli, Aránzazu and Takolander, Rabbe and Melander, Olle and Hamsten, Anders and Michoel, Tom and Skogsberg, Josefin}},
  issn         = {{1553-7404}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS Genetics}},
  title        = {{Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.}},
  url          = {{https://lup.lub.lu.se/search/files/2306787/4645401}},
  doi          = {{10.1371/journal.pgen.1004201}},
  volume       = {{10}},
  year         = {{2014}},
}