Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

Liu, Kai; Fang, Changcun; Shen, Yuwen; Liu, Zhengqin; Zhang, Min; Ma, Bingbing; Pang, Xinyan

doi:10.18632/oncotarget.16448

Cited by 44 publications

(37 citation statements)

References 27 publications

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“…Previous studies demonstrated that the expression of HIF-1a which significantly increased in human thoracic and abdominal aortic aneurysm tissues, resulted from local hypoxia. 17,18 Consistent with previous studies and the animal study, significantly increased expression of HIF-1a was also observed in human TAD tissues compared with controls. Originally, HIF-1a has the effect of increasing LOX expression, but more importantly there is extensive activation of inflammation molecules in TAD tissue.…”

Section: Discussionsupporting

confidence: 90%

Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

Yang

Jiao

et al. 2020

European Journal of Vascular and Endovascular Surgery

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WHAT THIS PAPER ADDS Thoracic aortic dissection (TAD) is a life threatening cardiovascular disorder. Intermittent hypoxia (IH) triggers beneficial effects in multiple physiological systems, such as hypertension and coronary heart disease, in clinical and animal models. It was found that IH alleviates b-aminopropionitrile monofumarate induced TAD in C57BL/6 mice. Future studies should focus on the specific mechanism of thez protective role of IH and whether IH might be a treatment method for TAD. Objective: Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. Methods: b-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n ¼ 30) (21%e5% O 2 , 90 s/cycle, 10 h/day, IH þ BAPN group) or normoxia (n ¼ 30) (21% O 2 , 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O 2)/re-oxygenation (30 min, 21% O 2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1a and LOX via HIF-1a-siRNA. Results: It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1b, IL-6, cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1a. Conclusion: The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice.

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Section: Discussionsupporting

confidence: 90%

Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

Yang

Jiao

et al. 2020

European Journal of Vascular and Endovascular Surgery

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“…The HIF-1α protein is expressed in young VSMCs in vitro, while it is reduced in old VSMCs [96]. To date, HIF-1α has been involved in the proliferation, migration, and morphological changes of VSMCs [150,151]. The mechanism by which hypoxia induces HIF-1α expression in human VSMCs involves PI3K/Akt(PKB) and osteopontin, as well as suppression of the expression of some proteins, including AEG-1, α-SMA, and SM22α [150].…”

Section: Hif and Vascular Smooth Muscle Cellsmentioning

confidence: 99%

“…To date, HIF-1α has been involved in the proliferation, migration, and morphological changes of VSMCs [150,151]. The mechanism by which hypoxia induces HIF-1α expression in human VSMCs involves PI3K/Akt(PKB) and osteopontin, as well as suppression of the expression of some proteins, including AEG-1, α-SMA, and SM22α [150]. However, the main function of HIF-1α is the inhibition of the proliferation and migration of human VSMCs, indicating that HIF-1α induces VSMC phenotype switching [150].…”

Section: Hif and Vascular Smooth Muscle Cellsmentioning

confidence: 99%

“…The mechanism by which hypoxia induces HIF-1α expression in human VSMCs involves PI3K/Akt(PKB) and osteopontin, as well as suppression of the expression of some proteins, including AEG-1, α-SMA, and SM22α [150]. However, the main function of HIF-1α is the inhibition of the proliferation and migration of human VSMCs, indicating that HIF-1α induces VSMC phenotype switching [150]. However, stabilization of the HIF-1α protein in 9-month-old WT mice promoted increased endothelial permeability [152].…”

Section: Hif and Vascular Smooth Muscle Cellsmentioning

confidence: 99%

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Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Alique

Sánchez-López

Bodega

et al. 2020

Cells

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Aging is one of the hottest topics in biomedical research. Advances in research and medicine have helped to preserve human health, leading to an extension of life expectancy. However, the extension of life is an irreversible process that is accompanied by the development of aging-related conditions such as weakness, slower metabolism, and stiffness of vessels. It also debated that aging can be considered an actual disease with aging-derived comorbidities, including cancer or cardiovascular disease. Currently, cardiovascular disorders, including atherosclerosis, are considered as premature aging and represent the first causes of death in developed countries, accounting for 31% of annual deaths globally. Emerging evidence has identified hypoxia-inducible factor-1α as a critical transcription factor with an essential role in aging-related pathology, in particular, regulating cellular senescence associated with cardiovascular aging. In this review, we will focus on the regulation of senescence mediated by hypoxia-inducible factor-1α in age-related pathologies, with particular emphasis on the crosstalk between endothelial and vascular cells in age-associated atherosclerotic lesions. More specifically, we will focus on the characteristics and mechanisms by which cells within the vascular wall, including endothelial and vascular cells, achieve a senescent phenotype.

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“…VSMCs (Liu et al, 2017). Therefore, we examined whether PHI aggravates Pi-induced loss of smooth muscle-specific markers such as smooth muscle α-actin (ACTA-2), smooth muscle myosin heavy chain 11 (MYH11), and smooth muscle protein 22α (TAGLN).…”

Section: Phi Decreases Smooth Muscle-specific Marker Expressionmentioning

confidence: 99%

Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate

et al. 2020

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Vascular calcification is a life-threatening clinical condition in chronic kidney disease (CKD) and is associated with reduced zinc serum levels. Anemia is another frequent complication of CKD. Hypoxia-inducible factor (HIF) stabilizers, also known as HIF prolyl hydroxylase inhibitors (PHI), are promising candidates to treat CKD-associated anemia by increasing erythropoietin synthesis. Recent evidence suggests that HIFs play a pivotal role in vascular calcification. Our study explored feasible impacts of HIF PHI on phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs) and tested whether zinc might inhibit this mineralization process. Treatment of VSMCs with PHI aggravated Pi-induced calcium deposition and Pi uptake. PHI promoted Pi-induced loss of smooth muscle cell markers (ACTA-2, MYH11, SM22α) and enhanced osteochondrogenic gene expression (Msx-2, BMP-2, Sp7) triggering osteochondrogenic phenotypic switch of VSMCs. These effects of PHI paralleled with increased pyruvate dehydrogenase kinase 4 (PDK4) expression, decreased Runx2 Ser451 phosphorylation, and reduced cell viability. Zinc inhibited Pi-induced mineralization of VSMCs in a dose-dependent manner and also attenuated the procalcification effect of PHI in Pi-induced mineralization. Zinc inhibited osteochondrogenic phenotypic switch of VSMCs reflected by lowering Pi uptake, decreasing the expressions of Msx-2, BMP-2, and Sp7 as well as the loss of smooth muscle cellspecific markers. Zinc preserved phosphorylation state of Runx2 Ser451, decreased PDK4 level, and restored cell viability. PHI alone reduced the expression of smooth muscle markers without inducing mineralization, which was also inhibited by zinc. In addition, we observed a significantly lower serum zinc level in CKD as well as in patients undergoing carotid endarterectomy compared to healthy individuals. Conclusion-PHI promoted the loss of smooth muscle markers and augmented

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Hypoxia-inducible factor 1a induces phenotype switch of human aortic vascular smooth muscle cell through PI3K/AKT/AEG-1 signaling

Cited by 44 publications

References 27 publications

Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

Intermittent Hypoxia Alleviates β-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL/6 Mice

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

Zinc Inhibits HIF-Prolyl Hydroxylase Inhibitor-Aggravated VSMC Calcification Induced by High Phosphate

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