Transcriptional profiling uncovers a network of cholesterol-responsive atherosclerosis target genes

• Published in: PLoS genetics 2008-03, Vol.4 (3), p.e1000036-e1000036
• Main Authors: Skogsberg, Josefin, Lundström, Jesper, Kovacs, Alexander, Nilsson, Roland, Noori, Peri, Maleki, Shohreh, Köhler, Marina, Hamsten, Anders, Tegnér, Jesper, Björkegren, Johan
• Format: Article
• Language: English
• Subjects: Animals; Apolipoprotein B-100 - genetics; Atherosclerosis; Atherosclerosis - etiology; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Cardiovascular disease; Cardiovascular Disorders/Valvular Disease; Cardiovascular Disorders/Vascular Biology; Carrier Proteins - genetics; Cholesterol; Cholesterol - metabolism; Computational Biology/Genomics; Computational Biology/Systems Biology; Experiments; Foam Cells - metabolism; Gene expression; Gene Expression Profiling; Genetics and Genomics/Animal Genetics; Genetics and Genomics/Bioinformatics; Genetics and Genomics/Disease Models; Genetics and Genomics/Functional Genomics; Genetics and Genomics/Gene Expression; Genetics and Genomics/Medical Genetics; Genomes; Heart attacks; Humans; Lipids; Lipoproteins; Macrophages - metabolism; Medicin och hälsovetenskap; Mice; Mice, Knockout; Mice, Mutant Strains; Mortality; Oligonucleotide Array Sequence Analysis; Plasma; Receptors, LDL - deficiency; Receptors, LDL - genetics; Reverse engineering; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Statins; Stroke; TECHNOLOGY; TEKNIKVETENSKAP
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1000036

Despite the well-documented effects of plasma lipid lowering regimes halting atherosclerosis lesion development and reducing morbidity and mortality of coronary artery disease and stroke, the transcriptional response in the atherosclerotic lesion mediating these beneficial effects has not yet been carefully investigated. We performed transcriptional profiling at 10-week intervals in atherosclerosis-prone mice with human-like hypercholesterolemia and a genetic switch to lower plasma lipoproteins (Ldlr(-/-)Apo(100/100)Mttp(flox/flox) Mx1-Cre). Atherosclerotic lesions progressed slowly at first, then expanded rapidly, and plateaued after advanced lesions formed. Analysis of lesion expression profiles indicated that accumulation of lipid-poor macrophages reached a point that led to the rapid expansion phase with accelerated foam-cell formation and inflammation, an interpretation supported by lesion histology. Genetic lowering of plasma cholesterol (e.g., lipoproteins) at this point all together prevented the formation of advanced plaques and parallel transcriptional profiling of the atherosclerotic arterial wall identified 37 cholesterol-responsive genes mediating this effect. Validation by siRNA-inhibition in macrophages incubated with acetylated-LDL revealed a network of eight cholesterol-responsive atherosclerosis genes regulating cholesterol-ester accumulation. Taken together, we have identified a network of atherosclerosis genes that in response to plasma cholesterol-lowering prevents the formation of advanced plaques. This network should be of interest for the development of novel atherosclerosis therapies.