Dataset Information

EGLN1 Inhibition and Rerouting of ?-Ketoglutarate Suffice for Remote Ischemic Protection.

ABSTRACT: Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (?KG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating ?KG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.

SUBMITTER: Olenchock BA

PROVIDER: S-EPMC4819986 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection.

Olenchock Benjamin A BA Moslehi Javid J Baik Alan H AH Davidson Shawn M SM Williams Jeremy J Gibson William J WJ Chakraborty Abhishek A AA Pierce Kerry A KA Miller Christine M CM Hanse Eric A EA Kelekar Ameeta A Sullivan Lucas B LB Wagers Amy J AJ Clish Clary B CB Vander Heiden Matthew G MG Kaelin William G WG

Cell 20160201 5

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (αKG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemi ...[more]

PMID: 26919427

Similar Datasets

Project description:Rationale: Remote ischemic perconditioning during cerebral ischemia (RIPerC) refers to the application of brief episodes of transient limb ischemia commonly to a limb, it represents a new safe, simple and low-cost paradigm in neuroprotection. Aim and/or Hypothesis: To evaluate the effects of RIPerC on acute ischemic stroke (AIS) patients, applied in the ambulance, to improve functional outcomes compared with standard of care. Sample Size Estimates: A sample size of 286 patients in each arm achieves 80% power to detect treatment differences of 14% in the outcome, using a two-sided binomial test at significance level of 0.05, assuming that 40% of the control patients will experience good outcome and an initial misdiagnosis rate of 29%. Methods and Design: We aim to conduct a multicentre study of pre-hospital RIPerC application in AIS patients. A total of 572 adult patients diagnosed of suspected clinical stroke within 8 h of symptom onset and clinical deficit >0 according to prehospital rapid arterial occlusion evaluation (RACE) scale score will be randomized, in blocks of size 4, to RIPerC or sham. Patients will be stratified by RACE score scale. RIPerC will be started in the ambulance before hospital admission and continued in the hospital if necessary. It will consist of five cycles of electronic tourniquet inflation and deflation (5 min each). The cuff pressure for RIPerC will be 200 mmHg during inflation. Sham will only simulate vibration of the device. Study Outcome(s): The primary outcome will be the difference in the proportion of patients with good outcomes as defined by a mRS score of 2 or less at 90 days. Secondary outcomes to be monitored will include early neurological improvement rate, treatment related serious adverse event rates, size of the infarct volume, symptomatic intracranial hemorrhage, metabolomic and lipidomic response to RIPerC and Neuropsychological evaluation at 90 days. Discussion: Neuroprotective therapies could not only increase the benefits of available reperfusion therapies among AIS patients but also provide an option for patients who are not candidates for these treatments. REMOTE-CAT will investigate the clinical benefit of RIC as a new neuroprotective strategy in AIS. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03375762.

Dataset Information

EGLN1 Inhibition and Rerouting of ?-Ketoglutarate Suffice for Remote Ischemic Protection.

Publications

EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets