Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease

Fialho, Maria da Luz Sousa; Jamil, Amira Hajirah Abd; Stannard, George A.; Heather, Lisa C.

doi:10.1016/j.bbadis.2018.09.024

Cited by 74 publications

(49 citation statements)

References 158 publications

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“…In response to hypoxia and its direct impact on cell metabolism, the cell induces the expression of a large number of genes. In particular, hypoxia-inducible factor 1 (HIF-1) is a transcriptional heterodimer composed of an α-subunit (HIF-1α) and a β-subunit (HIF-1β) ( Sousa Fialho et al, 2019 ). In normoxic conditions, the HIF-1α subunit is generated in the cytosol and degraded in an oxygen-dependent manner ( Salceda, 1997 ).…”

Section: Introductionmentioning

confidence: 99%

Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1

Liu¹,

Galli

Wang

et al. 2020

Front. Physiol.

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Insufficient oxygen availability (hypoxia) is a precursor to numerous cardiovascular diseases, including atherosclerosis, pulmonary hypertension, and heart failure. The main site of hypoxic injury in the human body is the mitochondria, where oxygen acts as the final electron acceptor in the process of oxidative phosphorylation. Hypoxia-inducible factor (HIF) is activated in hypoxic conditions and acts as an important modulator of diverse target genes in the human body. The downstream genes of HIF include vital modulators of cardiovascular-related signaling pathways. Therefore, it is hypothesized that HIF represents a potential therapeutic target for the treatment and prevention of cardiovascular diseases. In this short review, we introduce the pathophysiology of hypoxic injury in cardiovascular disease, and we conclude from convincing evidence that HIF can modulate relevant cardioprotective signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1

Liu¹,

Galli

Wang

et al. 2020

Front. Physiol.

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“…Advanced glycation end products (AGEs) interacting with a cell surface receptor, RAGE was reported to evoke in ammatory and thrombogenic reactions, which contributed to the development of CHD [56]. Research found that AGE/RAGE induced the activation of the ERK/MAPK signaling pathway, ultimately leading to activate nuclear factor NF-κB, thus increasing production of proin ammatory and proatherogenic mediators [57]. Moreover, regulating the AGE/RAGE pathway may be able to treat cardiac ischemic-reperfusion injury, diabetic cardiomyopathy, and in ammatory heart diseases [58].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Analysis to Reveal the Molecular Mechanism of Zhizi-Danshen on Coronary Heart Disease

Shen¹,

Wang²,

Wu³

et al. 2020

Preprint

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ObjectiveOur study aimed to investigate the potential mechanisms of the herb pair Zhizi-Danshen (ZD) for coronary heart disease (CHD) using network pharmacological data mining technology.MethodsThe Traditional Chinese Medicine System Pharmacology (TCMSP) database was used to collect the active ingredients of ZD and predict ZD-related target proteins. Afterwards, we identified CHD-related targets from DisGeNET database, NCBI gene database, and TTD database. The common targets both from ZD and CHD were screened by Venny2.1, which were then imported into the String database for protein-protein interaction (PPI) analysis. Finally, the GO and KEGG enrichment analysis were performed by R software, and the network construction was established using Cytoscape3.7.2.ResultsWe obtained 199 possible targets from 62 candidate ingredients of ZD and 1033 CHD-ralated targets, with 83 overlapping common target genes. Then, 11 core targets were acquired from PPI network analysis. Further, GO analysis showed that these common targets mainly influenced receptor ligand activity，cytokine activity，cytokine receptor binding，steroid hormone receptor activity, and peptide binding. KEGG pathway analysis indicated that ZD affected CHD through seven important pathways linked to vascular endothelial function regulation (fluid shear stress and atherosclerosis，AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway), imflammatory effects (IL-17 signaling pathway, TNF signaling pathway，Toll-like receptor signaling pathway)，and hormone regulation (relaxin signaling pathway). ConclusionsThis study revealed the potential pharmacological mechanisms of ZD against CHD, which were mainly associated with regulation of vascular endothelial function and inflammatory effects, promotion of vasodilatation, and prevention of cardiac fibrosis. Moreover, it provided a novel conception for the development of alternative therapies on CHD.

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“…HIF-1α and HIF-1β are the two subunits of HIF-1, in which HIF-1α subunit plays the central role in protecting cells from local hypoxia by increasing expression of its downstream target genes in many cardiovascular diseases [5] . The target genes of HIF-1α are those involved in angiogenesis, vascular reactivity (including secreted factors and cell surface receptors) and glucose metabolism (including metabolic enzymes, transporters and mitochondrial proteins) [6,33].…”

Section: Discussionmentioning

confidence: 99%

“…The most common cause of IHD is myocardial ischemia, a pathological state that can't supply adequate blood, which leads to the ischemic and hypoxic injury of myocardium [2][3][4]. Hypoxia, that is, the reduction of available oxygen, has a huge impact on the metabolism of the heart and then changes the normal heart function [5].…”

Section: Introductionmentioning

confidence: 99%

Septin4 Aggravates Hypoxia-Induced Cardiomyocytes Injury by Promoting HIF-1α Ubiquitination and Degradation through VHL

Zhang

You

et al. 2020

Preprint

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Backgrounds: Myocardial ischemia, characterized by insufficient nutrients and oxygen supply, is the most common cause of ischemic heart disease. Hypoxia-induced cardiomyocytes injury is the pathogenic feature of myocardial ischemia. Although previous studies have reported that the proapoptotic protein Septin4 contributes to prevent some cancers by promoting tumor cells apoptosis mainly through X-linked inhibitors of apoptosis (XIAPs), little is known its role in hypoxia-induced cardiomyocytes injury and its other new interacting partner. Results: In the current study, Septin4 is found to be involved in cardiomyocytes injury to hypoxia. The overexpression of Septin4 significantly aggravated hypoxic cardiomyocytes apoptosis assessed by cell viability assay and flow cytometry analysis. Mechanistically, hypoxia-inducible factor 1 alpha (HIF-1α) is confirmed as a novel protein mainly binding with GTPase domain of Septin4 by co-immunoprecipitation. Additionally, we found that the protective factor HIF-1α is down-regulated by Septin4 and the underlying mechanism is the von Hippel-Lindau protein (VHL)-mediated ubiquitin-proteasome degradation. Conclusions: These findings suggest that Septin4 aggravates hypoxia-induced cardiomyocytes injury by promoting HIF-1α ubiquitination and degradation by targeting to VHL, which may be beneficial to provide effective strategies for clinical treatment of myocardial ischemia and ischemic heart disease.

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Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease

Cited by 74 publications

References 158 publications

Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1

Novel Therapeutic Targets for Hypoxia-Related Cardiovascular Diseases: The Role of HIF-1

A Network Pharmacology Analysis to Reveal the Molecular Mechanism of Zhizi-Danshen on Coronary Heart Disease

Septin4 Aggravates Hypoxia-Induced Cardiomyocytes Injury by Promoting HIF-1α Ubiquitination and Degradation through VHL

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