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

Abstract

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.

Effect of hypoxia factors gene silencing on ROS production and metabolic status of A375 malignant melanoma cells

“…We observed a significant increase in ATP-linked respiration, H + -leak, and reverse capacity. Increased OXPHOS mediated by HIFs attenuation leads to increased mitochondrial biogenesis 81 , 82 . An increase in OXPHOS may also be a manifestation of cell adaptation to the conditions that have arisen, leading to de novo resistance of melanoma cells to inhibitors of the MAPK pathway and subsequently to oxidative stress, so-called combination of inhibition of the MAPK pathway and OXPHOS 37 .…”

Communications Between Bone Marrow Macrophages and Bone Cells in Bone Remodeling

“…If macrophages in part of the femoral head are polarized to the M1 phenotype and upregulate a large number of inflammatory mediators, they can promote bone cell apoptosis and accelerate femoral head necrosis (Figure 2) (Jin et al, 2020). In summary, bone formation relies on the interaction of a variety of cells which reminded above and other cytokines including HIF-1α (Karshovska et al, 2020)and CSF-1 (Alexander et al, 2011;Raggatt et al, 2014)to maintain the dynamic balance of the skeletal environment.…”

Non-coding RNAs in necroptosis, pyroptosis and ferroptosis in cancer metastasis

“… miR-500a-3p MLKL hsa-miR-500a-3P was obviously decreased in cisplatin-treated human tubular epithelial (HK2) cells, which significantly alleviated kidney injury by regulating MLKL-mediated necroptosis [ 48 ]. miR-210 HIF-3α E-cadherin HIF-1alpha promoted necroptosis of macrophages by upregulating miR-210 in lesional macrophages [ 49 ]. Overexpression of miR-210 promoted cancer metastasis of breast cancer [ 143 ], bladder cancer [ 144 ], renal cell carcinoma [ 145 ], hepatocellular carcinoma [ 146 ] and colorectal cancer [ 147 ].…”