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

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

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2018, 38(2): 324-334.

DOI：10.1161/ATVBAHA.117.310455

• atherosclerosis
• foam cells
• inflammation
• macrophages

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 alpha/beta II-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 alpha/beta II-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.

• 出版日期2018-2