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Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
- Source :
-
PLoS genetics [PLoS Genet] 2014 Feb 27; Vol. 10 (2), pp. e1004201. Date of Electronic Publication: 2014 Feb 27 (Print Publication: 2014). - Publication Year :
- 2014
-
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.
- Subjects :
- Animals
Aorta drug effects
Apolipoproteins B genetics
Atherosclerosis drug therapy
Atherosclerosis pathology
Gene Expression Regulation drug effects
Histone-Lysine N-Methyltransferase biosynthesis
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors administration & dosage
Mice
Mice, Transgenic
Nuclear Proteins biosynthesis
Ribonucleoproteins biosynthesis
Serine-Arginine Splicing Factors
Aorta metabolism
Atherosclerosis blood
Cholesterol blood
Receptors, LDL genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 10
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 24586211
- Full Text :
- https://doi.org/10.1371/journal.pgen.1004201