Myeloid-Specific Deletion of the AMPK alpha 2 Subunit Alters Monocyte Protein Expression and Atherogenesis

Fisslthaler, Beate; Zippel, Nina; Malik, Randa Abdel; Lagos, Fredy Delgado; Zukunft, Sven; Thoele, Janina; Siuda, Daniel; Soehnlein, Oliver; Wittig, Ilka; Heidler, Juliana; Weigert, Andreas und Fleming, Ingrid (2019): Myeloid-Specific Deletion of the AMPK alpha 2 Subunit Alters Monocyte Protein Expression and Atherogenesis. In: International Journal of Molecular Sciences, Bd. 20, Nr. 12, 3005

Abstract

The AMP-activated protein kinase (AMPK) is an energy sensing kinase that is activated by a drop in cellular ATP levels. Although several studies have addressed the role of the AMPK alpha 1 subunit in monocytes and macrophages, little is known about the alpha 2 subunit. The aim of this study was to assess the consequences of AMPK alpha 2 deletion on protein expression in monocytes/macrophages, as well as on atherogenesis. A proteomics approach was applied to bone marrow derived monocytes from wild-type mice versus mice specifically lacking AMPK alpha 2 in myeloid cells (AMPK alpha 2(MC) mice). This revealed differentially expressed proteins, including methyltransferases. Indeed, AMPK alpha 2 deletion in macrophages increased the ratio of S-adenosyl methionine to S-adenosyl homocysteine and increased global DNA cytosine methylation. Also, methylation of the vascular endothelial growth factor and matrix metalloproteinase-9 (MMP9) genes was increased in macrophages from AMPK alpha 2(MC) mice, and correlated with their decreased expression. To link these findings with an in vivo phenotype, AMPK alpha 2(MC) mice were crossed onto the ApoE(-/-) background and fed a western diet. ApoExAMPK alpha 2(MC) mice developed smaller atherosclerotic plaques than their ApoEx alpha 2(fl/fl) littermates, that contained fewer macrophages and less MMP9 than plaques from ApoEx alpha 2(fl/fl) littermates. These results indicate that the AMPK alpha 2 subunit in myeloid cells influences DNA methylation and thus protein expression and contributes to the development of atherosclerotic plaques.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1422-0067
• Sprache: Englisch