HIF-1α (Hypoxia-Inducible Factor-1α) Promotes Macrophage Necroptosis by Regulating miR-210 and miR-383

Objective: Inflammatory activation changes the mitochondrial function of macrophages from oxidative phosphorylation to reactive oxygen species production, which may promote necrotic core formation in atherosclerotic lesions. In hypoxic and cancer cells, HIF-1α (hypoxia-inducible factor) promotes oxygen-independent energy production by microRNAs. Therefore, we studied the role of HIF-1α in the regulation of macrophage energy metabolism in the context of atherosclerosis. Approach and Results: Myeloid cell–specific deletion ofHif1a reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis in apolipoprotein E-deficient mice. In inflammatory bone marrow–derived macrophages, deletion ofHif1a increased oxidative phosphorylation, ATP levels, and the expression of genes encoding mitochondrial proteins and reduced reactive oxygen species production and necroptosis. microRNA expression profiling showed that HIF-1α upregulatesmiR-210 and downregulatesmiR-383 levels in lesional macrophages and inflammatory bone marrow–derived macrophages. In contrast tomiR-210 , which inhibited oxidative phosphorylation and enhanced mitochondrial reactive oxygen species production,miR-383 increased ATP levels and inhibited necroptosis. The effect of miR-210 was due to targeting 2,4-dienoyl-CoA reductase, which is essential in the β oxidation of unsaturated fatty acids.miR-383 affected the DNA damage repair pathway in bone marrow–derived macrophages by targeting poly(ADP-ribose)-glycohydrolase (Parg), which reduced energy consumption and increased cell survival. Blocking the targeting of Parg bymiR-383 prevented the protective effect ofHif1a deletion in macrophages on atherosclerosis and necrotic core formation in mice.Conclusions: Our findings unveil a new mechanism by which activation of HIF-1α in inflammatory macrophages increases necroptosis through microRNA-mediated ATP depletion, thus increasing atherosclerosis by necrotic core formation.