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

microRNA在动脉粥样硬化过程中HIF-1α介导的巨噬细胞能量代谢调节中的作用

基本信息

批准号：
298934349
负责人：
Dr. Lucia Natarelli, since 5/2019
金额：
--
依托单位：
Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/298934349?language=en
关键词：
role microRNAs HIF 1alpha mediated

项目摘要

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.

巨噬细胞是先天性免疫反应的关键效应细胞，在慢性炎症性疾病中发挥重要作用，如动脉粥样硬化和肥胖相关的糖尿病，这些疾病导致全世界高达30%的死亡。巨噬细胞的深刻可塑性范围从促炎到抗炎亚型，使这些细胞能够调节炎症的不同阶段。转录因子缺氧诱导转录因子（HIF）-1 α通过将能量代谢从氧化磷酸化（OXPHOS）转变为有氧糖酵解来诱导促炎性M1巨噬细胞表型。然而，HIF-1 α诱导代谢向有氧糖酵解转变的潜在机制以及这种转变如何调节巨噬细胞功能目前尚不清楚。我们的初步研究结果表明，HIF-1 α缺乏在巨噬细胞上调OXPHOS和关键酶有关的氧化能量代谢，并减少坏死性细胞死亡。HIF-1 α敲除的这种效应与miR-210表达减少和miR-383表达增加有关。此外，巨噬细胞中的HIF-1 α敲除限制了动脉粥样硬化并减少了非凋亡性细胞死亡。我们推测HIF-1 α通过调节miR-210和miR-383的表达促进炎性巨噬细胞的坏死性凋亡并增加动脉粥样硬化。miR-210介导的OXPHOS抑制和ATP耗竭的协同效应可能在HIF-1 α诱导的巨噬细胞坏死性凋亡中起关键作用，这是由于在缺乏miR-383的情况下氧化DNA损伤的修复效率低下所致。为了验证这一假设，我们将在巨噬细胞中进行功能获得和丧失实验，以确定miR-210对OXPHOS、ATP合成、活性氧产生和氧化性DNA损伤的影响。此外，我们还将研究HIF-1 α抑制miR-383表达是否会通过去抑制其假定的靶聚（ADP-核糖）糖水解酶来增加ATP消耗。此外，我们将研究miR-210和miR-383在动脉粥样硬化过程中HIF-1 α介导的巨噬细胞死亡中的作用。我们相信这项研究将为慢性炎症性疾病中巨噬细胞能量代谢和存活的调节提供新的见解。因此，我们的目标是开发新的治疗策略，通过miRNA介导的代谢重编程来调节巨噬细胞功能。