Hypoxia Regulates mTORC1-Mediated Keratinocyte Motility and Migration via the AMPK Pathway

Yan, Tiantian; Zhang, Junhui; Tang, Di; Zhang, Xingyue; Jiang, Xupin; Zhao, Liping; Zhang, Qiong; Zhang, Dongxia; Huang, Yuesheng

doi:10.1371/journal.pone.0169155

Cited by 18 publications

(19 citation statements)

References 40 publications

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“…Hypoxia has been recognized as one of the prominent micro-environmental factors in tissue injury [32] and wound healing for decades [3, 33]; however, the effect of hypoxia on wound healing remains controversial [23, 34-37]. As skin seed cells, EpSCs and their offspring undergo slow, rhythmic processes of proliferation and differentiation in physiological conditions.…”

Section: Discussionmentioning

confidence: 99%

FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

Tang

Zhang

Yan

et al. 2018

Cell Physiol Biochem

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Background/Aims: Regional hypoxia promptly develops after trauma because of microvascular injury and increased oxygen consumption. This acute hypoxia plays a positive role in early skin wound healing. One of the mechanisms underlying the beneficial effects of acute hypoxia on wound healing may be increased hypoxia-inducible factor-1 (HIF-1α) expression. HIF-1α may affect the wound-healing process through many aspects, including angiogenesis, metabolism, and extra-cellular matrix synthesis and remodelling. Epidermal stem cells (EpSCs) are important participants in wound repair; however, whether these cells are regulated by hypoxia is unclear. This study aimed to elucidate the regulatory mechanism by which hypoxia acts on EpSCs. Methods: CCK8 assays, western blots and live cell station observation were employed to compare the viability, proliferation and motility of EpSCs cultured under normoxic conditions (21% O₂) with those cultured under hypoxic conditions (2% O₂). Moreover, we used FG-4592 (a prolyl hydroxylase inhibitor that stabilizes HIF-1α in normoxia), KC7F2 (a selective inhibitor of HIF-1α transcription) and siRNA against HIF-1α to regulate HIF-1α expression. Results: Acute hypoxia caused EpSCs to switch from a quiescent state to an activated state with higher viability and motility, as well as an earlier proliferation peak. We demonstrated that the HIF-1 signalling pathway mediated hypoxia-induced activation of EpSCs. Finally, the in vivo experiments showed that exogenous FG-4592 effectively accelerates wound healing, shortens healing times and even induces epidermal hyperplasia. Conclusion: This study demonstrated that both hypoxia and exogenous FG-4592 improve EpSC proliferation and motility by stabilizing HIF-1α, and its results suggest that HIF-1α is an important target through which wound healing can be accelerated and that FG-4592 is a promising new drug for wound repair.

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Section: Discussionmentioning

confidence: 99%

FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

Tang

Zhang

Yan

et al. 2018

Cell Physiol Biochem

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“…Hence, ROCK inhibitors and AMPK activating agents are considered as new therapeutic targets. [18][19][20][21][22][23][24][25] Evaluating ROCK and AMPK pathways together can provide hints about therapeutic target selection in the pathologies in which endothelium function impairs.…”

Section: Discussionmentioning

confidence: 99%

“…Long periods of AMPK activation might cause modifications in protein synthesis via the modulation of transcription factors, like myocyte enhancer factor-2, mammalian target of rapamycin and eukaryotic elongation factor 2. 23 Antidiabetic agents, such as, metformin 24 , thiazolidinediones, glukagon like peptid-1 agonists, dipeptidyl peptidase-4 inhibitors, statins, adiponectin and the leptin hormone increase the AMPK activation. 25,26 Experimentally, 5-aminoimidazole-4-carboxamide ribonucleoside is used for the AMPK activation 24 , whereas the dorsomorphine (compound C) is used for the inhibition.…”

Section: Adenosine Monophosphate-activated Protein Kinase Pathwaymentioning

confidence: 99%

“…It therefore shows a vasoprotective effect. [25][26][27] It is thought that the vasoprotective effects of the therapeutic agents like, metformin 24 , thiazolidinediones and statins also occur via the AMPK activation. 21 AMPK activation causes the NO-mediated relaxation in the spontaneously hypertensive rats.…”

Section: Adenosine Monophosphate-activated Protein Kinase Pathwaymentioning

confidence: 99%

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Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses

Balcilar

Özakça

Altan

2017

tjps

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Vascular tonus is controlled by endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF) and endotheliumderived contracting factor (EDCF) under physiological circumstances. In pathological conditions, impairment of endothelium-derived relaxation can be caused by both decrease in EDRF release and increase in EDCF release. The increase in EDCF is observed with diseases such as hypertension and diabetes. The contribution of Rho-kinase and activated protein kinase (AMPK), which have opposite effects, to the increased EDCF responses was investigated. Rho-kinases are the effectors of Rho which is one of the small guanosine triphosphate-binding proteins. They increase cytosolic Ca +2 concentration and cause vascular smooth muscle to contract, keeping myosin light chain (MLC) in phosphorylated state by affecting myosin phosphatase target subunit which dephosphorylates the MLC. The activities of Rho-kinases increase with the increase of EDCF function. AMPK is the energy sensor of the cell. It provides a vasculoprotective effect by causing endothelium-dependent and endothelium-independent relaxation in smooth muscle. In contrast to Rho-kinase pathway activity, AMPK pathway activity decreases with diseases in which the EDCF function increases. In cases such as diabetes and hypertension that endothelial function impairs toward vasocontraction, it is considered that evaluating Rho-kinase and AMPK pathways which mediate contraction and relaxation in vascular smooth muscle respectively, would provide clues on choosing therapeutic target for pathologies in which endothelial dysfunction is observed. ÖZFizyolojik koşullarda vasküler tonus endotel kaynaklı rahatlatıcı faktörü (EDRF), endotel kaynaklı hiperpolarizasyon faktörü (EDHF) ve endotel kaynaklı kasılma faktörü (EDCF) tarafından kontrol edilmektedir. Patolojik durumlarda endotel kaynaklı gevşemenin azalması, EDRF üretimindeki azalmaya bağlı olabileceği gibi EDCF düzeyinin artmasına da bağlı olabilmektedir. EDCF hipertansiyon, diyabet gibi hastalıklarda artmaktadır. Diyabet, hipertansiyon gibi patolojik koşullarda artan EDCF yanıtına birbirine ters etki yapan Rho-kinaz ve aktive protein kinaz (AMPK) yolaklarının katkısı olabileceği düşünülmektedir. Rho-kinazlar küçük guanozin trifosfat-bağlı proteinlerden biri olan Rho'nun efektörüdür. Rho-kinazlar hafif zincir miyozini (MLC) defosforile eden miyozin fosfataz hedef altbirimine etki ederek MLC'nin fosforile halde kalmasının sağlayarak sitozolik Ca +2 konsantrasyonu artırır ve vasküler düz kasın kasılmasına neden olurlar. Rho-kinazların aktivitesi EDCF yanıtlarının arttığı hipertansiyon, kalp yetmezliği ve diyabet gibi hastalıklarda artmaktadır. AMPK ise hücrenin enerji sensörü olarak düşünülmektedir. Vasküler düz kasta endotel bağımlı ve bağımsız gevşemeyi sağlayarak vasküloprotektif etki sağlamaktadır. AMPK'nin aktivitesi Rho-kinaz yolağının aktivitesinin tersine EDCF fonksiyonunun arttığı hipertansiyon ve diyabet gibi hastalıklarda azalmaktadır. Endotel fonksiyonunun vazokonstriksiyon y...

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“…Newborn BALB/c mice were euthanized by cervical dislocation. Primary mouse keratinocytes were obtained as described by Yan et al (41) and then routinely cultured in keratinocyte serum-free medium (10725018; Thermo Fisher Scientific). Unless otherwise indicated, the experimental results were repeated and obtained from the HaCaT cells.…”

Section: Cell Culturementioning

confidence: 99%

Autophagy is required for the directed motility of keratinocytes driven by electric fields

Yan

Jiang

Lin³

et al. 2018

FASEB j.

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Endogenous wound electric fields (EFs), an important and fundamental occurrence of wound healing, profoundly influence the directed migration of keratinocytes. Although numerous studies have unveiled the signals responsible for EF‐biased direction, the mechanisms by which EFs promote keratinocyte motility remains to be elucidated. In our study, EFs enhanced the directed migratory speed of keratinocytes by inducing autophagic activity, thereby facilitating skin barrier restoration. Initially, we found that electrical signals directed keratinocytes to the cathode with enhanced motility parameters [i.e., trajectory distance, trajectory speed, displacement distance, and displacement speed (Td/t)] and more efficient migration (directionality and Td/t along the x axis, among others). Meanwhile, EFs induced a time‐dependent increase in autophagic activity in keratinocytes, with constant autophagic flux, accompanied by increased transcription of numerous autophagy‐related genes. Deficiency in Atg5, a key protein necessary for autophagosome formation, led to significant reduction of autophagy, which was accompanied by a substantial reduction in EF‐stimulated directed motility. These results demonstrated a causal relationship between autophagy and EF‐directed migratory speed. In addition, both cell migration under normal conditions and EF‐biased directionality were autophagy independent. Thus, our findings define autophagy as an important functional regulator of electrically enhanced directed motility, adding to a growing understanding of EFs.—Yan, T., Jiang, X., Lin, G., Tang, D., Zhang, J., Guo, X., Zhang, D., Zhang, Q., Jia, J., Huang, Y. Autophagy is required for the directed motility of keratinocytes driven by electric fields. FASEB J. 33, 3922–3935 (2019). http://www.fasebj.org

show abstract

Hypoxia Regulates mTORC1-Mediated Keratinocyte Motility and Migration via the AMPK Pathway

Cited by 18 publications

References 40 publications

FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

FG-4592 Accelerates Cutaneous Wound Healing by Epidermal Stem Cell Activation via HIF-1α Stabilization

Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses

Autophagy is required for the directed motility of keratinocytes driven by electric fields

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