The role of microRNAs in HIF-1alpha-mediated regulation of macrophage energy metabolism during atherosclerosis

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Macrophages are key effector cells of the innate immune response and play an essential role in chronic inflammatory diseases, such as atherosclerosis and obesity-related diabetes, which cause up to 30% of all deaths worldwide. The profound plasticity of macrophages ranges from pro- to anti-inflammatory subtypes enables these cells to regulate different stages of inflammation. The transcription factor hypoxia-inducible transcription factor (HIF)-1alpha induces a pro-inflammatory M1 macrophage phenotype by shifting energy metabolism from oxidative phosphorylation (OXPHOS) to aerobic glycolysis. However, the underlying mechanism, by which HIF-1alpha induces the metabolic shift to aerobic glycolysis and how this shift regulates macrophage function are currently unknown. Our preliminary results show that HIF-1alpha deficiency in macrophages upregulates OXPHOS and key enzymes related to oxidative energy metabolism, and decreases necroptotic cell death. This effect of HIF-1alpha knockout is associated with reduced miR-210 and increased miR-383 expression. Moreover, HIF-1alpha knockout in macrophages limits atherosclerosis and reduces non-apoptotic cell death. We hypothesize that HIF-1alpha promotes necroptosis of inflammatory macrophages and increases atherosclerosis by regulating the expression of miR-210 and miR-383. The synergistic effects of miR-210-mediated suppression of OXPHOS and ATP depletion due to inefficient repair of oxidative DNA damage in the absence of miR-383 may play a key role in HIF-1alpha induced macrophage necroptosis. To test this hypothesis, we will perform gain- and loss function experiments in macrophages to determine the effect of miR-210 on OXPHOS, ATP synthesis, the production of reactive oxygen species, and oxidative DNA damage. Moreover, we will investigate whether suppression of miR-383 expression by HIF-1alpha increases ATP consumption by derepressing its putative target poly (ADP-ribose) glycohydrolase. In addition, we will study the role of miR-210 and miR-383 in HIF-1alpha-mediated macrophage cell death during atherosclerosis. We believe that this study will provide new insights into the regulation of macrophage energy metabolism and survival in chronic inflammatory diseases. Thus, we aim to develop novel therapeutic strategies to modulate macrophage function by miRNA-mediated metabolic reprogramming.