title: Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
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.
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden ; Cardiovascular Genomics Group, Department of Pathological Anatomy and Forensic Medicine, University of Tartu, Tartu, Estonia ; Institute for Genomics and Multi-scale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden ; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Hägg
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Husain A
authors.initials: HA
authors.lastname: Talukdar
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi Asl
authors.affiliation: Cardiovascular Genomics Group, Department of Pathological Anatomy and Forensic Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Cedergren
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ming-Mei
authors.initials: MM
authors.lastname: Shang
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aránzazu
authors.initials: A
authors.lastname: Rossignoli
authors.affiliation: Department of Surgery, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rabbe
authors.initials: R
authors.lastname: Takolander
authors.affiliation: Department of Clinical Sciences, Hypertension & Cardiovascular Disease, Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Atherosclerosis Research Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany ; The Roslin Institute, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Michoel
authors.affiliation: Cardiovascular Genomics Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Josefin
authors.initials: J
authors.lastname: Skogsberg
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001055:Apolipoproteins B / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D002784:Cholesterol / Q000097:blood*; D005786:Gene Expression Regulation / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000096:biosynthesis; D011973:Receptors, LDL / Q000235:genetics*; D012261:Ribonucleoproteins / Q000096:biosynthesis; D000068103:Serine-Arginine Splicing Factors
chemical_list: D001055:Apolipoproteins B; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009687:Nuclear Proteins; D011973:Receptors, LDL; D012261:Ribonucleoproteins; C499372:SRSF2 protein, mouse; D000068103:Serine-Arginine Splicing Factors; D002784:Cholesterol; D011495:Histone-Lysine N-Methyltransferase; C539231:MLL5 protein, mouse