Macrophage-Associated Lipin-1 Enzymatic Activity Contributes to Modified Low-Density Lipoprotein-Induced Proinflammatory Signaling and Atherosclerosis

Aimee E. Vozenilek, Aaron R. Navratil, Jonette M. Green, David T. Coleman, Cassidy M.R. Blackburn, Alexandra C. Finney, Brenna H. Pearson, Roman Chrast, Brian N. Finck, Ronald L. Klein, A. Wayne Orr, Matthew D. Woolard

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Objective-Macrophage proinflammatory responses induced by modified low-density lipoproteins (modLDL) contribute to atherosclerotic progression. How modLDL causes macrophages to become proinflammatory is still enigmatic. Macrophage foam cell formation induced by modLDL requires glycerolipid synthesis. Lipin-1, a key enzyme in the glycerolipid synthesis pathway, contributes to modLDL-elicited macrophage proinflammatory responses in vitro. The objective of this study was to determine whether macrophage-Associated lipin-1 contributes to atherogenesis and to assess its role in modLDL-mediated signaling in macrophages. Approach and Results-We developed mice lacking lipin-1 in myeloid-derived cells and used adeno-Associated viral vector 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (adeno-Associated viral vector 8-proprotein convertase subtilisin/kexin type 9) to induce hypercholesterolemia and plaque formation. Mice lacking myeloid-Associated lipin-1 had reduced atherosclerotic burden compared with control mice despite similar plasma lipid levels. Stimulation of bone marrow-derived macrophages with modLDL activated a persistent protein kinase C/βII-extracellular receptor kinase1/2-jun proto-oncogene signaling cascade that contributed to macrophage proinflammatory responses that was dependent on lipin-1 enzymatic activity. Conclusions-Our data demonstrate that macrophage-Associated lipin-1 is atherogenic, likely through persistent activation of a protein kinase C/βII-extracellular receptor kinase1/2-jun proto-oncogene signaling cascade that contributes to foam cell proinflammatory responses. Taken together, these results suggest that modLDL-induced foam cell formation and modLDL-induced macrophage proinflammatory responses are not independent consequences of modLDL stimulation but rather are both directly influenced by enhanced lipid synthesis.

Original languageEnglish
Pages (from-to)324-334
Number of pages11
JournalArteriosclerosis, thrombosis, and vascular biology
Volume38
Issue number2
DOIs
StatePublished - Feb 1 2018

Keywords

  • atherosclerosis
  • foam cells
  • inflammation
  • macrophages

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    Vozenilek, A. E., Navratil, A. R., Green, J. M., Coleman, D. T., Blackburn, C. M. R., Finney, A. C., Pearson, B. H., Chrast, R., Finck, B. N., Klein, R. L., Orr, A. W., & Woolard, M. D. (2018). Macrophage-Associated Lipin-1 Enzymatic Activity Contributes to Modified Low-Density Lipoprotein-Induced Proinflammatory Signaling and Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology, 38(2), 324-334. https://doi.org/10.1161/ATVBAHA.117.310455