Dataset Information

KLF11 mediates PPAR? cerebrovascular protection in ischaemic stroke.

ABSTRACT: Peroxisome proliferator-activated receptor gamma (PPAR?) is emerging as a major regulator in neurological diseases. However, the role of (PPAR?) and its co-regulators in cerebrovascular endothelial dysfunction after stroke is unclear. Here, we have demonstrated that (PPAR?) activation by pioglitazone significantly inhibited both oxygen-glucose deprivation-induced cerebral vascular endothelial cell death and middle cerebral artery occlusion-triggered cerebrovascular damage. Consistent with this finding, selective (PPAR?) genetic deletion in vascular endothelial cells resulted in increased cerebrovascular permeability and brain infarction in mice after focal ischaemia. Moreover, we screened for (PPAR?) co-regulators using a genome-wide and high-throughput co-activation system and revealed KLF11 as a novel (PPAR?) co-regulator, which interacted with (PPAR?) and regulated its function in mouse cerebral vascular endothelial cell cultures. Interestingly, KLF11 was also found as a direct transcriptional target of (PPAR?). Furthermore, KLF11 genetic deficiency effectively abolished pioglitazone cytoprotection in mouse cerebral vascular endothelial cell cultures after oxygen-glucose deprivation, as well as pioglitazone-mediated cerebrovascular protection in a mouse middle cerebral artery occlusion model. Mechanistically, we demonstrated that KLF11 enhanced (PPAR?) transcriptional suppression of the pro-apoptotic microRNA-15a (miR-15a) gene, resulting in endothelial protection in cerebral vascular endothelial cell cultures and cerebral microvasculature after ischaemic stimuli. Taken together, our data demonstrate that recruitment of KLF11 as a novel (PPAR?) co-regulator plays a critical role in the cerebrovascular protection after ischaemic insults. It is anticipated that elucidating the coordinated actions of KLF11 and (PPAR?) will provide new insights into understanding the molecular mechanisms underlying (PPAR?) function in the cerebral vasculature and help to develop a novel therapeutic strategy for the treatment of stroke.

SUBMITTER: Yin KJ

PROVIDER: S-EPMC3613710 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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KLF11 mediates PPARγ cerebrovascular protection in ischaemic stroke.

Yin Ke-Jie KJ Fan Yanbo Y Hamblin Milton M Zhang Jifeng J Zhu Tainqing T Li Siming S Hawse John R JR Subramaniam Malayannan M Song Chao-Zhong CZ Urrutia Raul R Lin Jiandie D JD Chen Y Eugene YE

Brain : a journal of neurology 20130212 Pt 4

Peroxisome proliferator-activated receptor gamma (PPARγ) is emerging as a major regulator in neurological diseases. However, the role of (PPARγ) and its co-regulators in cerebrovascular endothelial dysfunction after stroke is unclear. Here, we have demonstrated that (PPARγ) activation by pioglitazone significantly inhibited both oxygen-glucose deprivation-induced cerebral vascular endothelial cell death and middle cerebral artery occlusion-triggered cerebrovascular damage. Consistent with this f ...[more]

PMID: 23408111

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Project description:BackgroundCerebrolysin is a mixture of low-molecular-weight peptides and amino acids derived from pigs' brain tissue, which has potential neuroprotective and neurotrophic properties. It is widely used in the treatment of acute ischaemic stroke in Russia, Eastern Europe, China, and other Asian and post-Soviet countries.ObjectivesTo assess the benefits and risks of cerebrolysin for treating acute ischaemic stroke.Search methodsIn May 2016 we searched the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE, Embase, Web of Science Core Collection, with Science Citation Index, LILACS, OpenGrey, and a number of Russian Databases. We also searched reference lists, ongoing trials registers and conference proceedings, and contacted the manufacturer of cerebrolysin, EVER Neuro Pharma GmbH (formerly Ebewe Pharma).Selection criteriaRandomised controlled trials (RCTs) comparing cerebrolysin, started within 48 hours of stroke onset and continued for any time, with placebo or no treatment in people with acute ischaemic stroke.Data collection and analysisTwo review authors independently applied inclusion criteria, assessed trial quality and risk of bias, and extracted data.Main resultsWe identified six RCTs (1501 participants) that met the inclusion criteria.We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians.None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset).All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence).Serious adverse events: two trials reported on this outcome, with 90% confidence cerebrolysin increased the risks of serious adverse events by at least one third compared to placebo: 62/589 in cerebrolysin group versus 46/600 in placebo group; RR 1.37 90% CI 1.01 to 1.86 (2 trials, 1189 participants, moderate-quality evidence).Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence).Authors' conclusionsThe findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence suggesting that serious adverse events may be more common with cerebrolysin use in acute ischaemic stroke.

Dataset Information

KLF11 mediates PPAR? cerebrovascular protection in ischaemic stroke.

Publications

KLF11 mediates PPARγ cerebrovascular protection in ischaemic stroke.

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