miRNAs regulate the HIF switch during hypoxia: a novel therapeutic target

Abstract

The decline of oxygen tension in the tissues below the physiological demand leads to the hypoxic adaptive response. This physiological consequence enables cells to recover from this cellular insult. Understanding the cellular pathways that mediate recovery from hypoxia is therefore critical for developing novel therapeutic approaches for cardiovascular diseases and cancer. The master regulators of oxygen homeostasis that control angiogenesis during hypoxia are hypoxia-inducible factors (HIFs). HIF-1 and HIF-2 function as transcriptional regulators and have both unique and overlapping target genes, whereas the role of HIF-3 is less clear. HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 and HIF-3 expressions begin during chronic hypoxia in human endothelium. When HIF-1 levels decline, HIF-2 and HIF-3 increase. This switch from HIF-1 to HIF-2 and HIF-3 signaling is required in order to adapt the endothelium to prolonged hypoxia. During prolonged hypoxia, the HIF-1 levels and activity are reduced, despite the lack of oxygen-dependent protein degradation. Although numerous protein factors have been proposed to modulate the HIF pathways, their application for HIF-targeted therapy is rather limited. Recently, the miRNAs that endogenously regulate gene expression via the RNA interference (RNAi) pathway have been shown to play critical roles in the hypoxia response pathways. Furthermore, these classes of RNAs provide therapeutic possibilities to selectively target HIFs and thus modulate the HIF switch. Here, we review the significance of the microRNAs on the relationship between the HIFs under both physiological and pathophysiological conditions.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9600-2) contains supplementary material, which is available to authorized users.

Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia

“…To take advantage of regulating endothelial adaptation to hypoxia as a possible therapeutic intervention, it is important to understand the molecular pathways governing this process and especially the separate and common roles of HIF-1 and HIF-2 in mediating cell recovery. Although numerous interactions have been proposed to explain hypoxic HIF-1a destabilization [reviewed in Serocki et al (21)], the majority of these studies were performed in cancer cells, and few were validated in normal ECs. Furthermore, most of the current studies followed the effects on HIF-1 and HIF-2 levels in a single type of EC.…”

“…8B, the EPAS1 39UTR is much less prone to ARE-dependent destabilization than HIF1A mRNA. Although, to date, numerous miRNAs were shown to directly destabilize HIF1A mRNA in ECs, no such miRNA has been identified for EPAS1 mRNA (21). Nevertheless, chronic hypoxia impairs dicer (DICER1) activity in a von Hippel-Lindau-dependent manner, and thus miRNA biogenesis affecting both HIF-a isoforms and, notably, EPAS1 mRNA is regulated by the dicer-dependent miRNA 185, which is down-regulated by hypoxia (51).…”

“…HIF-1 governs the acute adaptation to hypoxia, whereas HIF-2 activity begins later (1), and this creates a transitional switch between the 2 HIF proteins. The inability to reduce the HIF-1 levels during prolonged hypoxia leads to cell death (21). Numerous protein factors have been proposed to modulate the HIF transitional switch (22)(23)(24) [reviewed in Serocki et al (21)], and the mechanisms underlying the HIF switch remain poorly understood.…”

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

“…The expression of HIFα mRNA and proteins can be regulated by the expression of microRNAs (miRs), also called hypoxamiRs when induced under hypoxic conditions. miRs downregulate the expression of specific target mRNAs by decreasing the expression of the transcript levels or by repressing translation . During early hypoxia, miRs will induce the accumulation of HIF1α, while maintaining HIF2α and HIF3α at steady‐state levels.…”

The Roles of Hypoxia-Inducible Factors and Non-Coding RNAs in Gastrointestinal Cancer

“…Although small molecules have been widely developed as HIF regulators, many recent studies have proposed the use of miRNA-based approaches for regulating HIFs [72]. The detailed mechanisms via which miRNAs control HIF-1α expression can be divided into direct and indirect regulation.…”