title: Differential regulation of aldose reductase expression during macrophage polarization depends on hyperglycemia.
abstract: Aldose reductase (AR; gene AKR1B1) is the rate-limiting enzyme of the polyol pathway and has been associated with diabetes and atherosclerosis. Here, we sought to identify the mechanisms underlying differential AR expression in human atherosclerotic plaque macrophages. In vitro, M1-polarized human monocyte-derived macrophages expressed significantly higher levels of AKR1B1 mRNA and AR protein compared with M2-polarized macrophages. AR activity was significantly higher in M1 macrophages. AKR1B1 mRNA expression correlated positively with the M1 marker TNF(r = 0.430,P = 0.006) and negatively with the M2 marker MRC1 (r = -0.443,P = 0.044). Increased AR expression in M1 macrophages depended on hyperglycemia. Concomitantly, expression of SLC2A1 (coding for the Glc transporter GLUT-1) was significantly higher in M1 than in M2 macrophages. Pharmacological inhibition of GLUT-1 using STF-32 completely abrogated Glc-induced AR up-regulation in M1 macrophages. When analyzing AR expression in post-mortem coronary artery plaque macrophages, a history of diabetes was associated with a significantly increased proportion of CD68(+)AR(++)macrophages, supporting the in vivo relevance of our in vitro findings. We demonstrate that the phenotype of atherosclerotic plaque macrophages may be affected by cardiovascular risk factors such as hyperglycemia. Our data illustrate the complex interplay between systemic and local factors in atherogenesis.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany christian.gleissner@med.uni-heidelberg.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Rupp
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Domschke
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Linden
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Mohammadreza
authors.initials: M
authors.lastname: Akhavanpoor
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Andreas O
authors.initials: AO
authors.lastname: Doesch
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, Heidelberg, Germany.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gleissner
mesh_terms: D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology; D003920:Diabetes Mellitus / Q000276:immunology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008562:Membrane Glycoproteins; D058226:Plaque, Atherosclerotic / Q000276:immunology*; D011971:Receptors, Immunologic / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000449:Aldehyde Reductase; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005947:Glucose; D051272:Glucose Transporter Type 1; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C573543:MRC1 protein, human
keywords: Atherosclerosis; aldose reductase; coronary artery disease; diabetes mellitus; macrophage