Normoxic induction of cerebral HIF-1α by acetazolamide in rats: Role of acidosis

Xu, Jiajun; Peng, Zhaoyun; Li, Runping; Dou, Tonghai; Xu, Wei; Gu, Guojun; Liu, Yun; Kang, Zhiwei; Tao, Hengyi; Zhang, Junyi; Ostrowski, Robert P.; Lü, Jing; Sun, Xuejun

doi:10.1016/j.neulet.2009.01.008

Cited by 28 publications

(13 citation statements)

References 24 publications

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“…It is well known that AZA treatment induces metabolic acidosis via carbonic anhydrase inhibition [48], and thus, we propose that AZA stabilizes HIF-1α through acidosis mediated von Hippel-Lindau protein nucleolar sequestration and subsequent dysfunction. Consistent with our hypothesis, Xu et al [49] reported that AZA significantly induced cerebral HIF-1α under normoxic condition, and acidosis played an important role. Secondly, we cannot rule out the possibility that AZA increases HIF-1α expression through, at least in part, modulating PHDs, which hydroxylate HIF-1α leading to its degradation [50,51].…”

Section: Discussionsupporting

confidence: 92%

Hypoxia-Inducible Factor-1a Dependent Pathways Mediate the Renoprotective Role of Acetazolamide Against Renal Ischemia-Reperfusion Injury

An¹,

Zhang

Han

et al. 2013

Cell Physiol Biochem

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Background/Aims: Acute kidney injury (AKI) is a major complication of kidney transplantation, resulting in early graft dysfunction. Since diuretic acetazolamide (AZA) has been shown to improve contrast induced AKI, we hypothesized that AZA also protected against ischemia-reperfusion (I/R) caused AKI. Methods: An in vivo mouse renal I/R injury model and an in vitro H₂O₂ stimulated HK-2 cell injury model were utilized to examine the renoprotective effect of AZA. Renal injury and blood flow were measured. Nitric oxide synthase (eNOS)/Nitric oxide (NO), cell apoptosis and hypoxia-inducible factor-1α (HIF-1α) changes were analyzed. Results: AZA reduced kidney injury scores and improved renal function by decreasing serum creatinine and BUN levels after I/R. Impaired renal blood flow was restored by increasing eNOS activities and NO production, as indicated by Laser Doppler imaging. TUNEL staining presented that AZA reduced apoptotic cells due to attenuated caspase activation and increased Bcl-2/Bax ratio. Furthermore, HIF-1α induction by AZA was demonstrated. AZA also enhanced in vitro NO production, reduced cell apoptosis and increased HIF-1α expression. Knockdown of HIF-1α by RNAi confirmed that AZA exerted its protective role depending on HIF-1α. AZA's effects were significantly reduced by Akt inhibitor LY294002. Conclusions: The present study demonstrated that AZA exerted a renoprotective role against I/R induced AKI through activating HIF-1α and downstream pathways.

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Section: Discussionsupporting

confidence: 92%

Hypoxia-Inducible Factor-1a Dependent Pathways Mediate the Renoprotective Role of Acetazolamide Against Renal Ischemia-Reperfusion Injury

An¹,

Zhang

Han

et al. 2013

Cell Physiol Biochem

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“…A recent study has shown that hypoxia stimulated HIF-Iα caused phenotypic switch in fibroblasts to myofibroblasts through metalloproteinase-2 signaling pathway with relevance to myointimal hyperplasia [19]. HIF-Iα also gets stabilized under normoxic conditions to perform similar functions [20][21][22][23]. In this perspective, transgenic expression of Ang-1 stabilized HIF-Iα protein in db/db mouse hearts which rescued the impaired endogenous angiogenic growth factors [24].…”

Section: Discussionmentioning

confidence: 96%

Non-hypoxic stabilization of HIF-Iα during coordinated interaction between Akt and angiopoietin-1 enhances endothelial commitment of bone marrow stem cells

et al. 2012

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We previously reported that mesenchymal stem cells (MSC) co-expressing Akt and angiopoietin-1 (Ang-1) preserved infarcted heart function via angiomyogenesis. The present study determined the mechanism of co-overexpression of Akt and Ang-1 in promoting endothelial commitment of MSC. The cells were transduced with vectors encoding for Akt ((Akt)MSC), Ang-1 ((Ang-1)MSC), and both Akt and Ang-1 ((AA)MSC) using Empty vector transduced MSC ((Emp)MSC) as control. Molecular studies indicated a coordinated interaction between Akt and Ang-1 in (AA)MSC and led to non-hypoxic stabilization of hypoxia inducible factor-1α (HIF-Iα) which accentuated under 4-h anoxia. We also observed HIF-Iα dependent induction of hemeoxygenase-1, endothelial specific markers and VEGF in (AA)MSC. Vascular commitment of (AA)MSC was confirmed by immunostaining, Western blotting and flow cytometry for endothelial specific early and late markers including Flt1, Flk1, Tie2, VCAM-1, and von Willebrand Factor-VIII (vWF-VIII) in HIF-Iα dependent fashion besides exhibiting higher emigrational activity and angiogenesis in vitro. (AA)MSC transplanted into rat model of myocardial infarction showed higher Flk1 and Flt1 positivity and also promoted intrinsic Flk1(+) and Flt1(+) cell mobilization into the infarcted heart. Given the ease of availability of MSC and simplicity of approach to co-overexpress Ang-1 and Akt to enhance their endothelial commitment, the strategy will be significant for cellular angiogenesis to treat ischemic heart.

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“…The hemorrhagic transformation may involve hypoxia‐inducible factor‐1(HIF‐1) and its downstream genes, including vascular endothelial growth factor (VEGF) and matrix metalloproteinase‐2 (MMP‐2), both of which are related to vascular permeability. Acidosis and free radicals are known to up‐regulate HIF‐1, which may be involved in hyperglycemia‐enhanced blood–brain barrier (BBB) degeneration (Xu et al, 2009). HIF‐1 is a heterodimeric transcriptional complex composed of oxygen‐regulated inducible HIF‐1α subunit and constitutive HIF‐1β subunit.…”

mentioning

confidence: 99%

Suppression of hypoxia‐inducible factor‐1α and its downstream genes reduces acute hyperglycemia‐enhanced hemorrhagic transformation in a rat model of cerebral ischemia

Chen

Ostrowski

Zhou

et al. 2010

J of Neuroscience Research

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We evaluated a role of hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream genes in acute hyperglycemia-induced hemorrhagic transformation in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats weighing 280-300 g (n = 105) were divided into sham, 90 min middle cerebral artery occlusion (MCAO), MCAO plus HIF-1alpha inhibitors, 2-methoxyestradiol (2ME2) or 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), groups. Rats received an injection of 50% dextrose (6 ml/kg intraperitoneally) at 15 min before MCAO. HIF-1alpha inhibitors were administered at the onset of reperfusion. The animals were examined for neurological deficits and sacrificed at 6, 12, 24, and 72 hr following MCAO. The cerebral tissues were collected for histology, zymography, and Western blot analysis. The expression of HIF-1alpha was increased in ischemic brain tissues after MCAO and reduced by HIF-1alpha inhibitors. In addition, 2ME2 reduced the expression of vascular endothelial growth factor (VEGF) and the elevation of active matrix metalloproteinase-2 and -9 (MMP-2/MMP-9) in the ipsilateral hemisphere. Both 2ME2 and YC-1 reduced infarct volume and ameliorated neurological deficits. However, only 2ME2 attenuated hemorrhagic transformation in the ischemic territory. In conclusion, the inhibition of HIF-1alpha and its downstream genes attenuates hemorrhagic conversion of cerebral infarction and ameliorates neurological deficits after focal cerebral ischemia.

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Normoxic induction of cerebral HIF-1α by acetazolamide in rats: Role of acidosis

Cited by 28 publications

References 24 publications

Hypoxia-Inducible Factor-1a Dependent Pathways Mediate the Renoprotective Role of Acetazolamide Against Renal Ischemia-Reperfusion Injury

Hypoxia-Inducible Factor-1a Dependent Pathways Mediate the Renoprotective Role of Acetazolamide Against Renal Ischemia-Reperfusion Injury

Non-hypoxic stabilization of HIF-Iα during coordinated interaction between Akt and angiopoietin-1 enhances endothelial commitment of bone marrow stem cells

Suppression of hypoxia‐inducible factor‐1α and its downstream genes reduces acute hyperglycemia‐enhanced hemorrhagic transformation in a rat model of cerebral ischemia

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