title: Diet-induced (epigenetic) changes in bone marrow augment atherosclerosis.
abstract: Alterations in DNA methylation patterns in peripheral blood leukocytes precede atherosclerotic lesion development in mouse models of atherosclerosis and have been linked to cardiovascular death in patients. The aim of this study is to investigate the long-term changes induced by WTD feeding on BM cells and the consequences for atherosclerosis susceptibility. Hereto, WTD BM or Chow BM was transplanted into LDLR KO mice on chow. BM from WTD BM recipient mice exhibited hypomethylation of CpG regions in the genes encoding Pu.1 and IRF8, key regulators of monocyte proliferation and macrophage differentiation. In agreement, in blood, the numbers of leukocytes were 40% (P<0.05) higher as a result of an increase in F4/80(+) monocytes (3.4-fold; P<0.01). An increase of CD11c(++) cells was also found (2.4-fold; P<0.05). Furthermore, spleens were enlarged, and the percentage of F4/80(+) cells expressing CD86 was induced (1.8-fold; P<0.01), indicating increased activation of splenic macrophages. Importantly, mice reconstituted with WTD BM showed a significant, 1.4-fold (P<0.05) increase in aortic root plaque size in the absence of changes in serum cholesterol. We conclude that WTD challenge induces transplantable epigenetic changes in BM, alterations in the hematopoietic system, and increased susceptibility to atherosclerosis. Manipulation of the epigenome, when used in conjunction with blood lipid reduction, could thus prove beneficial to treat cardiovascular disorders.
authors.affiliation: Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands evankampen@lacdr.leidenuniv.nl.
authors.forename: Erik
authors.initials: E
authors.lastname: van Kampen
authors.affiliation: Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands.
authors.forename: Armand
authors.initials: A
authors.lastname: Jaminon
authors.affiliation: Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands.
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.affiliation: Division of Biopharmaceutics, Cluster of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, The Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D001772:Blood Cell Count; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D019175:DNA Methylation; D004032:Diet; D066273:Diet, Western / Q000009:adverse effects; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D006410:Hematopoiesis / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D011973:Receptors, LDL; D014157:Transcription Factors
keywords: CpG island; DNA methylation; IRF8; Pu.1; hematopoiesis; macrophage