Neuronal deficiency of HIF prolyl 4-hydroxylase 2 in mice improves ischemic stroke recovery in an HIF dependent manner

Li, Lexiao; Saliba, Pamela; Reischl, Stefan; Marti, Hugo H.; Kunze, Reiner

doi:10.1016/j.nbd.2016.03.018

Cited by 40 publications

(30 citation statements)

References 57 publications

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“…This suggests that thiamine deficiency and hypoxic stress may exhibit a common adaptive regulatory mechanism centralizing through HIF-1α activation. Further studies are warranted to understand the role of HIF-1α in adaptive thiamine homeostasis during malignant and non-malignant conditions associated with thiamine deficiency and hypoxic stress such as diabetes, Wernicke-Korsakoff Syndrome, and cerebrovascular ischemic stroke (53–57). …”

Section: 0 Discussionmentioning

confidence: 99%

Role of HIF-1α in the hypoxia inducible expression of the thiamine transporter, SLC19A3

Zera

Sweet

Zastre

2016

Gene

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Ensuring continuous intracellular supply of thiamine is essential to maintain metabolism. Cellular homeostasis requires the function of the membrane bound thiamine transporters THTR1 and THTR2. In the absence of increased dietary intake of thiamine, varying intracellular levels to meet metabolic demands during pathophysiological stressors, such as hypoxia, requires adaptive regulatory mechanisms to increase thiamine transport capacity. Previous work has established the up-regulation of SLC19A3 (THTR2) gene expression and activity during hypoxic stress through the activity of the hypoxia inducible transcription factor 1 alpha (HIF-1α). However, it is unknown whether HIF-1α acts directly or indirectly to trans-activate expression of SLC19A3. This work utilized the breast cancer cell line BT-474 treated with 1% O2 or a hypoxia chemical mimetic deferoxamine to determine the minimal promoter region of SLC19A3 responsible for hypoxia responsiveness. In silico sequence analysis determined two contiguous hypoxia responsive elements in close proximity to the transcriptional start site of the SLC19A3 gene. Using a HIF-1α transcriptional factor ELISA assay, HIF-1α was capable of binding to a dsDNA construct of the SLC19A3 minimal promoter. Chromatin immunoprecipitation assay established that SP1 was bound to the SLC19A3 minimal promoter region under normoxic conditions. However, HIF-1α binding to the minimal promoter region occurred during hypoxic treatments, while no SP1 binding was observed under these conditions. This work demonstrates the direct binding and activation of SLC19A3 expression by HIF-1α during hypoxic stress, suggesting an important adaptive regulatory role for HIF-1α in maintaining thiamine homeostasis.

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Section: 0 Discussionmentioning

confidence: 99%

Role of HIF-1α in the hypoxia inducible expression of the thiamine transporter, SLC19A3

Zera

Sweet

Zastre

2016

Gene

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“…The total infarct volume in mm3, therefore, were calculated by ΣI ∗ 0.4 in which the 0.4 means the distance between neighbor two sections in mm. This equation was used to correct for the increase in volume of the ipsilateral hemisphere due to edema-induced swelling 24.…”

Section: Methodsmentioning

confidence: 99%

Lyophilized Powder of Catalpol and Puerarin Protected Cerebral Vessels from Ischemia by Its Anti-apoptosis on Endothelial Cells

Liu¹,

Tang²,

Shao³

et al. 2017

Int. J. Biol. Sci.

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Catalpol and puerarin are two monomers of Rehmannia glutinosa and Lobed Kudzuvine Root, which are two herbs commonly used together in ancient prescriptions of traditional Chinese medicine for cerebral ischemia. Our previous study shows that the lyophilized powder of the two monomers improved the outcome of cerebral ischemia excellently in rodents. However, if it protects vessels from ischemia is unknown. The present research studied the protection of lyophilized powder of catalpol and puerarin (CP) on endothelial cells and the relative mechanism in vivo and in vitro. Middle cerebral artery occlusion (MCAO) rats were used to study the improvement of CP on neurological deficiency, regional cerebral blood flow (rCBF), and infarct volume. The morphology of vessels and the apoptosis of brain vascular endothelial cells (BVECs) were observed and detected by immunohistochemistry approaches. To study how CP protected primary BVECs (pBVECs) from ischemic penumbra, oxygen glucose deprivation (OGD)-damaged pBVECs were cultured in the condition of insufficient nutrition and low oxygen which recapitulate the low perfusion of ischemic penumbra. Using the cell model, the mechanism by which CP protected pBVECs was studied by shRNA and pathway inhibitors. CP at the dose of 65.4 mg/kg increased regional cerebral blood flow (rCBF), reduced infarct volume, protected vessel integrity and inhibited endothelial cell apoptosis in vivo. But it only improved rCBF, vessel integrity and BVECs apoptosis at the dose of 32.7 mg/kg. In vitro, the protection of CP on pBVECs was proved to be ERK/HIF-1a- and PI3K/AKT/mTOR/HIF-1a-dependent. This study indicates a possibility of CP being a new drug for cerebral ischemia. Besides, this research provides an alternative cell model for penumbra ECs study.

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“…Our major finding is that neuronal inactivation of PHD2 in mice improves recovery from cerebral ischemia [2, 3]. One could hypothesize that this protective effect is either a direct one or alternatively occurs in an indirect manner, whereby PHD2 deficient neurons produce factors that act in a paracrine fashion on neighboring endothelial cells, astrocytes or microglia.…”

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confidence: 99%

“…PHD2 inactivation in neurons resulted in HIF stabilization and subsequent transcriptional activation of erythropoietin and vascular endothelial growth factor (VEGF) [2, 3]. Both mediators are well known to be potent anti-apoptotic factors, which directly support neuronal survival.…”

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Oxygen sensors and neuronal adaptation to ischemia

Marti

Kunze

2016

Oncotarget

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Neuronal deficiency of HIF prolyl 4-hydroxylase 2 in mice improves ischemic stroke recovery in an HIF dependent manner

Cited by 40 publications

References 57 publications

Role of HIF-1α in the hypoxia inducible expression of the thiamine transporter, SLC19A3

Role of HIF-1α in the hypoxia inducible expression of the thiamine transporter, SLC19A3

Lyophilized Powder of Catalpol and Puerarin Protected Cerebral Vessels from Ischemia by Its Anti-apoptosis on Endothelial Cells

Oxygen sensors and neuronal adaptation to ischemia

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