Hypoxia inducible factor as a therapeutic target for atherosclerosis

Jain, Tanmay; Nikolopoulou, Eleni Aliki; Xu, Qingbo; Qu, Aijuan

doi:10.1016/j.pharmthera.2017.09.003

Cited by 166 publications

(148 citation statements)

References 116 publications

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“…Hypoxia-inducible factors (HIFs) act as transcriptional activators to mediate cellular response to hypoxia [6]. HIF-1 is a heterodimeric protein, and it is one of the key regulators in a low-oxygen environment [7]. HIF-1α, a HIF-1 subunit, is involved in some processes, including the adaptation to low concentration of oxygen and cellular survival [8].…”

Section: Introductionmentioning

confidence: 99%

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Shi¹,

Zhang²,

Hu³

et al. 2019

Pharmacology

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Background/Aims: Hypoxia can induce cell injury in cardiomyocytes and further lead to cardiovascular diseases. Genistein (Gen), the predominant isoflavone found in soy products, has shown protective effects on cardiovascular system. The aim of the present study was to investigate the cardioprotective effect of Gen against chemical hypoxia-induced injury. Methods: Cobalt chloride (CoCl₂) was administrated to trigger chemical hypoxia in H9c2 cardiomyocytes. Cell proliferation was detected by using MTT assay. The expression level of hypoxia-related proteins (hypoxia-inducible factor [HIF]-1α and Notch-1) and apoptosis-related proteins (B cell lymphoma [Bcl]-2, Bax, and caspase-3) were evaluated by Western blot analysis. Results: In response to hypoxia, cell viability was reduced dramatically, whereas the expression of HIF-1α was upregulated. Hypoxia also induced cardiomyocytes apoptosis by reducing the ratio of Bcl-2/Bax and increasing expression of caspase-3. Interestingly, Gen attenuated CoCl₂-induced cell death and suppressed HIF-1α expression, as well as upregulated the expression of Notch-1. Furthermore, Gen could antagonize CoCl₂-induced apoptosis through upregulating Bcl-2/Bax ratio and inhibiting caspase-3 expression. Conclusions: Gen prevents chemical hypoxia-induced cell apoptosis through inhibition of the mitochondrial apoptotic pathway, exerting protective effects on H9c2 cardiomyocytes.

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Section: Introductionmentioning

confidence: 99%

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Shi¹,

Zhang²,

Hu³

et al. 2019

Pharmacology

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“…In the current study, compared with that after simple muscle contusion, the increased mRNA expression of HIF-1α and VEGF in the initial stage of repair after macrophage depletion (Fig. 7a, b) might be because macrophage depletion mimicked hypoxia and triggered an increase in HIF-1α, thereby upregulating VEGF (59,(64)(65)(66)(67). However, VEGF mainly came from white blood cells in plasma (34,68,69); thus macrophage depletion led to the sustained reduction of VEGF.…”

Section: Igf-1 Injection Did Not Improve the Aggravated Muscle Brosismentioning

confidence: 54%

Impaired Skeletal Muscle Regeneration Induced by Macrophage Depletion could not be Improved by IGF-1 Injection

Zeng¹,

Liu²,

Zhao³

et al. 2020

Preprint

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Background: Our previous study found that the depletion of macrophages led to the downregulation of insulin-like growth factor 1 (IGF-1) and impaired muscle regeneration after contusion. It was speculated that IGF-1 injection might improve the muscle repair impairment induced by macrophage depletion. Therefore, we explored whether injected IGF-1 plays an important role in improving impaired muscle repair. Methods: Animal models of muscle contusion and macrophage depletion with and without IGF-1 injection were established with gastrocnemius muscles in mice. Comprehensive histomorphological and genetic analyses were performed on the contused muscles after macrophage depletion and IGF-1 injection. Results: IGF-1 injection could promote the partial recovery of macrophage subpopulations (CD206) and the expression of vascular endothelial growth factor (VEGF) and angiopoietin -1 (Angpt-1) after macrophage depletion. However, after IGF-1 injection, the levels of regenerative myofibers and fibrosis, as well as the levels of proinflammatory macrophages (CD68) and the expression of muscle differentiation factor (MyoD), myogenin, VEGF and Angpt-1 still did not return to the levels found after simple muscle contusion in the late stage of repair. Conclusions: These results suggest that IGF-1 injection did not improve the impaired regeneration and repair of contused muscles induced by macrophage depletion.

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“…[53,54] The common signaling pathways regulating immune and in ammatory responses in PD and AHS also include EGFR tyrosine kinase inhibitor resistance, TNF, PI3K Akt, toll like receptor, MAPK, JAK stat, cytokine cytokine receptor interaction and other signaling pathways [55][56][57][58][59][60] .HIF-1 signaling pathway has cell-speci c response to vascular endothelial cells, smooth muscle cells and macrophages. By up regulating VEGF, NO, ROS and PDGF, it can cause endothelial cell dysfunction, angiogenesis and in ammatory response, and affect glucose metabolism and blood oxygen content, [61] On the other hand, DCHD can reduce blood viscosity and brinogen level, inhibit platelet aggregation, promote thrombolysis, correct abnormal Hemorheology and increase effective circulation perfusion. The results are con rmed by each other.…”

Section: Discussionmentioning

confidence: 99%

Study on The Effect Mechanism of “Common Treatment for Different Diseases” of Dachaihu Decoction on Prediabetes and Acute Hemorrhagic Stroke Based on Network Pharmacology

Zhang¹,

Cao²,

Zhang³

et al. 2020

Preprint

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Background: In this study, network pharmacology method was used to systematically predict and analyze the mechanism of "Common treatment for different diseases" effect of Dachaihu Decoction(DCHD) in the treatment of Prediabetes(PD) and Acute hemorrhagic stroke(AHS).Methods: TCMsp (Traditional Chinese Medicine systems pharmacology database and analysis platform) database was used to collect all the candidate active components related to 8 kinds of traditional Chinese medicine of DCHD, and UniProt database was used to obtain the drug action target and construct the "traditional Chinese medicine -Compound -target" action network; Genecards, OMIM(Online Mendelian Inheritance in Man), DisGeNET, CTD(Comparative Toxicogenomics Database) and TTD（Therapeutic Target Database）databases were used to obtain the related genes of PD and AHS respectively, and the interaction analysis of Venn with potential active components was carried out to obtain the common target of DCHD in the treatment of the two diseases.Using STRING 11.0 and Cytoscape3.72 to analyze protein-protein interaction of common targets and screen key common targets. BioGPS was used to obtain the distribution information in organs and tissues, and the relationship between the molecules and the key functional molecules were described. Bioconductor (R) was used to analyze the gene ontology (go) enrichment and the pathway analysis of the Kyoto Encyclopedia of genes and genomes (KEGG), so as to systematically predict the mechanism of "Common treatment for different diseases" of DCHD for PD and AHS.Results: with OB ≥ 30% and DL ≥ 0.18 as the screening criteria, 133 active compounds were screened out and 1034 drug targets were obtained; There are 3878 PD gene targets, 2674 AHS gene targets, 129 drug disease common targets, and 10 key targets whose median value is greater than 18;The key common targets displayed by biogps are mainly distributed in CD33+_ Myeloid.2(degree = 4)，Prostate.2(degree = 3)，CD56+_ NKCells.1(degree = 3)，Lung.2(degree = 3)，CD56+_ Nkcells. 2 (degree = 2);2281 biological processes, 65 cell components and 142 molecular functions were obtained by GO functional enrichment analysis;161 signal pathways were obtained by KEGG enrichment analysis, and the ones with higher proportion were AGE-RAGE signaling pathway in diabetic complications,PI3K-Akt signaling pathway,TNF signaling pathway,IL-17 signaling pathway,MAPK signaling pathway,HIF-1 signaling pathway,Relaxin signaling pathwa,C-type lectin receptor signaling pathway,which is mainly related to oxidative stress, glycolipid metabolism, immune inflammatory response, and neuroendocrine.Conclusion: DCHD can achieve the effect of "Common treatment for different diseases" by acting on the common receptor of PD and AHS through multi-component, multi-target and multi-channel, providing reference for further experimental verification, potential pharmacological mechanism and clinical application.

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Hypoxia inducible factor as a therapeutic target for atherosclerosis

Cited by 166 publications

References 116 publications

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Genistein Protects H9c2 Cardiomyocytes against Chemical Hypoxia-Induced Injury via Inhibition of Apoptosis

Impaired Skeletal Muscle Regeneration Induced by Macrophage Depletion could not be Improved by IGF-1 Injection

Study on The Effect Mechanism of “Common Treatment for Different Diseases” of Dachaihu Decoction on Prediabetes and Acute Hemorrhagic Stroke Based on Network Pharmacology

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