In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.

The circulatory system distributes blood flow to each tissue and transports oxygen and nutrients. Peripheral circulation is required to maintain the physiological function in each tissue. Disturbance of circulation, therefore, decreases oxygen delivery, leading to tissue hypoxia which takes place in several cardiovascular disorders including atherosclerosis, pulmonary arterial hypertension and heart failure. While tissue hypoxia can be induced because of cardiovascular disorders, hypoxia signaling itself has a potential to modulate tissue remodeling processes or the severity of the cardiovascular disorders. Hypoxia inducible factor-1α (HIF-1α) and HIF-2α belongs to a group of transcription factors which mediate most of the cellular responses to hypoxia at a transcriptional level. We, and others, have reported that HIF-α signaling plays a critical role in the initiation or the regulation of inflammation. HIF-α signaling contributes to the tissue remodeling processes; thus it has a potential to become a therapeutic target. Elucidation of the molecular link, therefore, between hypoxia signaling and tissue remodeling will greatly help us to understand the pathophysiology of the cardiovascular disorders. The purpose of this review is to give a brief overview of the current understanding about the function HIF-α in inflammation processes especially by focusing on its roles in macrophages. In addition, the pathophysiological roles of hypoxia signaling for the development of cardiovascular disease will be discussed.

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6C hi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.