Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Vanderhaeghen, Tineke; Vandewalle, Jolien; Libert, Claude

doi:10.1111/febs.15222

Cited by 31 publications

(28 citation statements)

References 149 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hypoxia and in ammation are unequivocally linked 21 and are two of the main physiological consequences of SARS-CoV-2 infection, particularly in severe cases. In this study we present scRNAseq data regarding HIF1α-related gene expression in peripheral blood leukocytes from critically ill COVID-19 and characterized the different cell subpopulations.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

Taniguchi‐Ponciano

Vadillo

Mayani

et al. 2020

Preprint

View full text Add to dashboard Cite

Since its emergence, in December 2019, COVID-19 has resulted in more than 12 million people infected and has killed more than 570000. Hypoxemia has been identified as one of the main clinical manifestations of this disease, especially in severe cases. We have previously reported that in critically ill COVID-19 patients there is a shift towards an immature myeloid profile in peripheral blood cells, including band neutrophils, immature monocytes, metamyelocytes, monocyte-macrophages, monocytoid precursors, and promyelocytes-myelocytes, which, together with mature monocytes and segmented neutrophils, comprise the vast majority of blood cells in these patients. Such an immature myeloid profile may be the result of a physiological response known as emergency myelopoiesis. In the present study, we performed scRNAseq from leukocytes from five critically ill COVID-19 patients and characterized the expression of hypoxia-inducible factor1α (HIF1α) mRNA and its transcriptionally regulated genes. HIF1α is a master transcription factor involved in the cellular response to hypoxia. We herein report that these cellular subsets express high levels of HIF1α mRNA and several of their transcriptional targets, including those related to inflammation, such as CXCL8, CXCR1, CXCR2, and CXCR4; those potentially involved in virus sensing, such as TLR2 and TLR4; and those related to metabolism, such as SLC2A3, PFKFB3, PGK1, GAPDH and SOD2. The up-regulation and participation of HIF1α in relevant events such as inflammation, immunometabolism, and TLR make it a potential molecular marker for COVID-19 severity and, interestingly, could represent a potential target for molecular therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

Taniguchi‐Ponciano

Vadillo

Mayani

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Sirtuins also coordinate switch from glucose to fatty acid oxidation during this phase. The molecular mechanisms for this remain unclear [10,11,14,22,25]. With cell recovery, mitochondrial biogenesis is initiated and there are upregulation of markers of mitochondrial biogenesis such as PAR gamma coactivator-1α (PGC-1α), Transcription factor A for mitochondria (TFAM), and nuclear respiratory factors (NRF-1) [9,15,23].…”

Section: Role Of Hif-α/sirtuins In Sepsis (Fig 1)mentioning

confidence: 99%

“…During this initial hyper-inflammatory phase with associated tissue hypoxia, the PRR (Toll-like receptors) upregulate a number of proliferative pathways such as NF-ĸB, hyper activation of NLRP3 inflammasommes, mitogen-activated protein kinase (MAPK), and mammalian target of rapamycin (mTOR) that trigger the cytokine storm [ 23 – 25 ].…”

Section: Mitochondrial Dysfunction In Sepsis (Fig 1 mentioning

confidence: 99%

“…Biochemically, this phase is associated with reduced activity of HIF-α and upregulation of Sirtuin activity. Sirtuins with their deacetylase function inactivate NF-ĸB, HIF-α, high-mobility group box proteins-1 (HMBG-1), and other DAMP molecules, thus decreasing the overall cytokine load [ 23 – 25 ]. Sirtuins also coordinate switch from glucose to fatty acid oxidation during this phase.…”

Section: Mitochondrial Dysfunction In Sepsis (Fig 1 mentioning

confidence: 99%

“…The role HIF-α, as a biomarker, for severity in sepsis is unclear and continues to be investigated [ 10 – 12 , 25 ]. Sepsis is dynamic process and the levels of HIF-α may vary depending on the phase of the disease and also with the different pathogens [ 12 ].…”

Section: Future Directions: Potential Mitochondrial-related Diagnostimentioning

confidence: 99%

See 2 more Smart Citations

Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality

2020

View full text Add to dashboard Cite

Background Decline in mitochondrial function occurs with aging and may increase mortality. We discuss mitochondrial contribution to Covid-19 sepsis, specifically the complex interaction of innate immune function, viral replication, hyperinflammatory state, and HIF-α/Sirtuin pathways. Methods Articles from PubMed/Medline searches were reviewed using the combination of terms "SARS-CoV-2, Covid-19, sepsis, mitochondria, aging, and immunometabolism". Results Evidence indicates that mitochondria in senescent cells may be dysfunctional and unable to keep up with hypermetabolic demands associated with Covid-19 sepsis. Mitochondrial proteins may serve as damage-associated molecular pattern (DAMP) activating innate immunity. Disruption in normal oxidative phosphorylation pathways contributes to elevated ROS which activates sepsis cascade through HIF-α/Sirtuin pathway. Viral-mitochondrial interaction may be necessary for replication and increased viral load. Hypoxia and hyper-inflammatory state contribute to increased mortality associated with Covid-19 sepsis. Conclusions Aging is associated with worse outcomes in sepsis. Modulating Sirtuin activity is emerging as therapeutic agent in sepsis. HIF-α, levels of mitochondrial DNA, and other mitochondrial DAMP molecules may also serve as useful biomarker and need to be investigated. These mechanisms should be explored specifically for Covid-19-related sepsis. Understanding newly discovered regulatory mechanisms may lead to the development of novel diagnostic and therapeutic targets.

show abstract

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Locatelli

Minutolo²,

Nicola³

et al. 2022

Drugs

View full text Add to dashboard Cite

Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.

show abstract

Hypoxia‐inducible factors in metabolic reprogramming during sepsis

Cited by 31 publications

References 149 publications

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

Increased expression of hypoxia-induced factor 1α mRNA and its related genes in myeloid blood cells from critically ill COVID-19 patients

Coronavirus (Covid-19) sepsis: revisiting mitochondrial dysfunction in pathogenesis, aging, inflammation, and mortality

Evolving Strategies in the Treatment of Anaemia in Chronic Kidney Disease: The HIF-Prolyl Hydroxylase Inhibitors

Contact Info

Product

Resources

About