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

PLoS Genet. 2014 Feb 27;10(2):e1004201. doi: 10.1371/journal.pgen.1004201. eCollection 2014 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / metabolism*
  • Apolipoproteins B / genetics
  • Atherosclerosis / blood*
  • Atherosclerosis / drug therapy
  • Atherosclerosis / pathology
  • Cholesterol / blood*
  • Gene Expression Regulation / drug effects
  • Histone-Lysine N-Methyltransferase / biosynthesis
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / biosynthesis
  • Receptors, LDL / genetics*
  • Ribonucleoproteins / biosynthesis
  • Serine-Arginine Splicing Factors

Substances

  • Apolipoproteins B
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Nuclear Proteins
  • Receptors, LDL
  • Ribonucleoproteins
  • SRSF2 protein, mouse
  • Serine-Arginine Splicing Factors
  • Cholesterol
  • Histone-Lysine N-Methyltransferase
  • MLL5 protein, mouse

Grant support

This work was supported by the Swedish Research Council (521-2012-2581, 522-2007-5792, Josefin Skogsberg (JS), Johan L. M. BjÖrkegren (JLMB)), Swedish Heart-Lung Foundation (JLMB), the Torsten and Ragnar Söderberg foundation (AH), Swedish Society of Medicine (SLS-96281, SLS-249001, JS, JLMB), King Gustaf V and Queen Victoria‚s Foundation of Freemasons (JS, JLMB), Karolinska Institutet Foundations (JS, JLMB). This work was also supported by grant from University of Tartu (SP1GVARENG, JLMB), the Estonian Research Council (ETIS, ETF8853, JLMB), Clinical Gene Networks AB (collaboration agreement with Merck Inc. US), Astra Zeneca Translational Science Centre - Karolinska Institutet (joint research program in translational science), and the Department of Medical Biophysics and Biochemistry, Karolinska Institutet (JS, JLMB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.