Hypoxia signaling in human diseases and therapeutic targets

Abstract

Since the discovery of hypoxia-inducible factor (HIF), numerous studies on the hypoxia signaling pathway have been performed. The role of HIF stabilization during hypoxia has been extended from the induction of a single gene erythropoietin to the upregulation of a couple of hundred downstream targets, which demonstrates the complexity and importance of the HIF signaling pathway. Accordingly, HIF and its downstream targets are emerging as novel therapeutic options to treat various organ injuries. In this review, we discuss the current understanding of HIF signaling in four different organ systems, including the heart, lung, liver, and kidney. We also discuss the divergent roles of HIF in acute and chronic disease conditions and their revealed functions. Finally, we introduce some of the efforts that are being performed to translate our current knowledge in hypoxia signaling to clinical medicine.

Comorbid Chronic Diseases and Acute Organ Injuries Are Strongly Correlated with Disease Severity and Mortality among COVID-19 Patients: A Systemic Review and Meta-Analysis

“…Third, certain antiviral drugs such as chloroquine [62], ribavirin [63,68], and lopinavir/ritonavir [67] have side effects that can include organ damage. Fourth, acute respiratory distress syndrome-(ARDS-) induced hypoxia can promote damage in organs outside of the respiratory system [64,75]. Finally, secondary infection by other pathogens may contribute to acute organ damage [5].…”

“…Other drugs recommended for treating COVID-19, including interferon alpha and ribavirin, may also potentially cause cardiac damage [63]. Moreover, virus-induced cytokine storm and pneumonia-associated hypoxia may also contribute to the development ACI and/or the progression of ACI into heart failure in critically ill SARS-CoV-2-infected patients [64].…”

Non-Canonical Targets of HIF1a Drive Cell-Type-Specific Dysfunction

“…Molecular oxygen is crucial to support energy production of the cell, and low oxygen upregulates a rapid and conserved transcriptional response mediated largely by HIF transcription factors in all mammalian cells. HIF1a promotes an adaptive response by upregulating oxygen-independent metabolism and increasing blood vessel formation; however, chronic accumulation of HIF1a negatively impacts the function of almost every organ system (Kullmann et al, 2020; Lee et al, 2019; Menendez-Montes et al, 2016; Takubo et al, 2010).…”

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…The surviving cells and the inflammatory cells that have extravasated to the injured area experience hypoxia in oxygen deprived conditions. When the cells experience hypoxia, it stabilizes the transcription factor hypoxia inducible factor-1α (HIF-1α), which accumulates in the cell nucleus to direct gene expression towards helping one to address hypoxia [24,25]. Active HIF-1α signaling triggers the production of large number of angiogenic growth factors, among them vascular endothelial growth factor-A (VEGF-A) [24,25].…”

“…These soluble growth factors direct the sprouting of the new blood vessels, i.e. angiogenesis, to deliver oxygen and address the hypoxia in the tissue [24]. The abundance of angiogenic blood vessels in the granulation tissue (the loose connective tissue produced in the early phase of the healing period) is so abundant that the word "granulation tissue" is actually derived from the granular appearance of the angiogenic capillaries.…”