HIF-1α (Hypoxia-Inducible Factor-1α) Promotes Macrophage Necroptosis by Regulating miR-210 and miR-383
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Updated: Dec 29, 2025
Highly Efficient Transfection of Human THP-1 Macrophages by Nucleofection
Published on: September 2, 2014
Ela Karshovska1,2, Yuanyuan Wei1,2, Pallavi Subramanian1
1From Institute for Cardiovascular Prevention, University Hospital, Ludwig-Maximilians-University, Munich, Germany (E.K., Y.W., P.S., R.M., C.G., I.B., A.P., J.C.C., A.S.).
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 of Hif1a reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis in apolipoprotein E-deficient mice. In inflammatory bone marrow-derived macrophages, deletion of Hif1a 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 upregulates miR-210 and downregulates miR-383 levels in lesional macrophages and inflammatory bone marrow-derived macrophages. In contrast to miR-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 by miR-383 prevented the protective effect of Hif1a 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.
Insights
Hypoxia-inducible factor (HIF-1α) promotes atherosclerosis by altering macrophage energy metabolism and increasing necroptosis. Inhibiting HIF-1α in macrophages reduces this effect, offering a potential therapeutic target for cardiovascular disease.
Area of Science:
- Cardiovascular Biology
- Cellular Metabolism
- Molecular Medicine
Background:
- Inflammatory activation shifts macrophage mitochondrial function from oxidative phosphorylation to reactive oxygen species (ROS) production.
- This metabolic shift may contribute to the formation of necrotic cores in atherosclerotic lesions.
- Hypoxia-inducible factor (HIF-1α) is known to promote anaerobic energy production in hypoxic cells.
Purpose of the Study:
- To investigate the role of HIF-1α in regulating macrophage energy metabolism within the context of atherosclerosis.
- To elucidate the molecular mechanisms by which HIF-1α influences macrophage function and atherosclerotic plaque development.
Main Methods:
- Utilized apolipoprotein E-deficient mice with myeloid cell-specific deletion of Hif1a.
- Analyzed inflammatory bone marrow-derived macrophages for metabolic and functional changes.
- Performed microRNA expression profiling to identify HIF-1α-regulated microRNAs.
- Investigated the targets and functions of specific microRNAs (miR-210 and miR-383) in macrophage metabolism and survival.
Main Results:
- Myeloid-specific Hif1a deletion reduced atherosclerosis and necrotic core formation by limiting macrophage necroptosis.
- Hif1a deletion in macrophages increased oxidative phosphorylation, ATP levels, and mitochondrial gene expression, while decreasing ROS production and necroptosis.
- HIF-1α upregulates miR-210 (inhibiting oxidative phosphorylation and enhancing ROS) and downregulates miR-383 (increasing ATP and inhibiting necroptosis).
- miR-210 targets 2,4-dienoyl-CoA reductase, impacting fatty acid beta-oxidation.
- miR-383 targets poly(ADP-ribose)-glycohydrolase (Parg), affecting DNA damage repair and reducing energy consumption.
Conclusions:
- HIF-1α activation in inflammatory macrophages promotes necroptosis via microRNA-mediated ATP depletion.
- This mechanism contributes to atherosclerosis progression through increased necrotic core formation.
- Targeting HIF-1α or its downstream microRNAs presents a novel therapeutic strategy for atherosclerosis.
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