title: Transcriptional profiling uncovers a network of cholesterol-responsive atherosclerosis target genes.
abstract: 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.
authors: The Computational Medicine Group, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Josefin
authors: J
authors: Skogsberg
authors: Jesper
authors: J
authors: Lundström
authors: Alexander
authors: A
authors: Kovacs
authors: Roland
authors: R
authors: Nilsson
authors: Peri
authors: P
authors: Noori
authors: Shohreh
authors: S
authors: Maleki
authors: Marina
authors: M
authors: Köhler
authors: Anders
authors: A
authors: Hamsten
authors: Jesper
authors: J
authors: Tegnér
authors: Johan
authors: J
authors: Björkegren
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics
chemical_list: D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011973:Receptors, LDL; C106092:microsomal triglyceride transfer protein; D002784:Cholesterol