HIF‐1α Contributes to Hypoxia‐induced VSMC Proliferation and Migration by Regulating Autophagy in Type A Aortic Dissection

Huang, Ben; Chen, Nan; Chen, Zhenhang; Shen, Jinqiang; Zhang, Hao; Wang, Chunsheng; Sun, Yongxin

doi:10.1002/adbi.202300292

Cited by 2 publications

(3 citation statements)

References 42 publications

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“…Furthermore, we showed that chronic IH-induced autophagy and mitophagy, is not observed in HIF-1 α heterozygous mice demonstrating that IH-induced mitochondrial remodeling depends on HIF-1 upon IH. This aligns with the role of HIF-1 in inducing autophagy by activating the transcription of genes, including BNIP3 27,28 , one of the main autophagic receptor activated by hypoxia 30 . HIF-1 has also been shown to positively regulate parkin-mediated mitophagy in acute kidney injury 31 and in diabetes 32 .…”

Section: Discussionsupporting

confidence: 74%

“…Because chronic IH alters mitochondrial function and leads to cardiomyocytes apoptosis [13][14][15] , we first investigated if IH induced mitochondrial remodeling by evaluating autophagy and mitophagy. Since HIF-1 is recognized to activate genes encoding for the autophagic process 27,28 , we also questioned if IH-induced mitochondrial remodeling depends on HIF-1.…”

Section: Introductionmentioning

confidence: 99%

“…Because chronic IH alters mitochondrial function and leads to cardiomyocytes apoptosis 13-15 , we first investigated if IH induced mitochondrial remodeling by evaluating autophagy and mitophagy. Since HIF-1 is recognized to activate genes encoding for the autophagic process 27,28 , we also questioned if IH-induced mitochondrial remodeling depends on HIF-1. Then, considering that AMPK activation has been demonstrated to be involved in myocardial response to mitochondrial stress, we questioned its myocardial activation state under chronic IH.…”

Section: Introductionmentioning

confidence: 99%

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Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α

Moulin,

Blachot-Minassian,

Kneppers

et al. 2024

Preprint

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Chronic intermittent hypoxia (IH), a major feature of obstructive sleep apnea syndrome (OSA), is associated with a more severe myocardial infarction. In this study, we performed RNA sequencing of cardiac samples from mice exposed to IH, which reveals a specific transcriptomic signature of the disease, relative to mitochondrial remodeling and cell death. Corresponding to its activation under chronic IH, we stabilized the Hypoxia Inducible Factor-1a (HIF-1a) in cardiac cells in vitro, and observed its association with an increased autophagic flux. In accordance, IH induced autophagy and mitophagy that is decreased in HIF-1a+/_ mice compared to wild-type animals suggesting that HIF-1 plays a significant role in IH-induced mitochondrial remodeling. Next, we showed that the AMPK metabolic sensor, typically activated by mitochondrial stress, is inhibited after 3 weeks of IH in hearts. Therefore, we assessed the effect of metformin, an anti-diabetic drug and potent activator of AMPK, on myocardial response to ischemia-reperfusion (I/R) injury. Daily administration of metformin significantly decreases infarct size without any systemic beneficial effect on insulin-resistance under IH conditions. The cardioprotective effect of metformin is lost in AMPKa2 knock-out mice demonstrating that AMPKa2 isoform promotes metformin-induced cardioprotection in mice exposed to IH. Mechanistically, we found that metformin inhibits IH-induced mitophagy in myocardium and decreases HIF-1a nuclear expression in mice subjected to IH. In vitro demonstrated that metformin induces HIF-1a phosphorylation, decreases its nuclear localization and subsequently HIF-1 transcriptional activity. Collectively, these results identify the AMPKa2 metabolic sensor as a novel modulator of HIF-1 activity. Our data suggest that metformin could be considered as a cardioprotective drug in OSA patients independently of their metabolic status.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α

Moulin,

Blachot-Minassian,

Kneppers

et al. 2024

Preprint

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Identifying HIF1A and HGF as two hub genes in aortic dissection and function analysis by integrating RNA sequencing and single-cell RNA sequencing data

Li,

Liu,

Mao

et al. 2024

Front. Cardiovasc. Med.

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ObjectiveAortic dissection (AD) is a severe aortic disease with high mortality, and its pathogenesis remains elusive. To explore the regulatory mechanisms of AD, we integrated public RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) datasets to screen the hub genes of AD and further analyzed their functions, which may provide references to the diagnosis and treatment of AD.MethodsFour AD-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis and differential expression analysis were applied to identify overlapping genes in dataset GSE153434. Protein–protein interaction (PPI) network was constructed based on overlapping genes. Five methods (closeness, degree, EPC, MCC, and MNN) were used to pick hub genes. The receiver operating characteristic curve was used to evaluate the diagnostic efficiency of the hub genes in extra datasets GSE98770 and GSE52093. scRNA-seq dataset GSE213740 was used to explore the expression and function of the hub genes at the single-cell level. Quantitative real-time polymerase chain reaction was used to verify the expression of hub genes in beta-aminopropionitrile (BAPN)-induced mouse thoracic aortic aneurysm and dissection (TAAD) model.ResultsA total of 71 overlapping genes were screened by intersecting the significant genes in the pink module and the differentially expressed genes. A PPI network with 45 nodes and 74 edges was generated, and five top hub genes (HIF1A, HGF, HMOX1, ITGA5, and ITGB3) were identified. All the hub genes had area under the curve values above 0.55. scRNA-seq data analysis showed that HIF1A was significantly upregulated in macrophages and HGF was significantly upregulated in vascular smooth muscle cells (SMCs) of the ascending aortas in AD patients. HIF1A may transcriptionally regulate multiple downstream target genes involving inflammation (TLR2, ALOX5AP, and MIF), glycolysis (ENO1, LDHA, and GAPDH), tissue remodeling (PLAU), and angiogenesis (SERPIN and VEGFA). HGF may participate in the signaling among SMCs, fibroblasts, and endothelial cells through binding to different receptors (MET, EGFR, IGF1R, and KDR). The mRNA expression of Hif1a, Hgf, and their target genes, including Alox5ap, Serpine1, Tlr2, Plau, Egfr, and Igf1r, was significantly upregulated in aortic tissues of BAPN-treated mice.ConclusionBy integrating RNA-seq and scRNA-seq data, we identified HIF1A and HGF as two hub genes with good diagnostic efficiency for AD. HIF1A in macrophages may promote AD formation by promoting inflammation, glycolysis, tissue remodeling, and angiogenesis, and HGF may mediate signaling among SMCs, fibroblasts, and endothelial cells in the development of AD.

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HIF‐1α Contributes to Hypoxia‐induced VSMC Proliferation and Migration by Regulating Autophagy in Type A Aortic Dissection

Cited by 2 publications

References 42 publications

Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α

Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α

Identifying HIF1A and HGF as two hub genes in aortic dissection and function analysis by integrating RNA sequencing and single-cell RNA sequencing data

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