Journal article
Prohibitin‐1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis
Journal of the American Heart Association, Vol.10(14), pp.e019877-e019877
07/20/2021
DOI: 10.1161/JAHA.120.019877
PMCID: PMC8483490
PMID: 34219469
Abstract
Background In sepsis, circulating cytokines and lipopolysaccharide elicit mitochondrial dysfunction and cardiomyopathy, a major cause of morbidity and mortality with this condition. Emerging research places the PHB1 (lipid raft protein prohibitin‐1) at the nexus of inflammation, metabolism, and oxidative stress. PHB1 has also been reported in circulation, though its function in this compartment is completely unknown. Methods and Results Using a wide‐ranging approach across multiple in vitro and in vivo models, we interrogated the functional role of intracellular and circulating PHB1 in the heart during sepsis, and elucidated some of the mechanisms involved. Upon endotoxin challenge or sepsis induction in rodent models, PHB1 translocates from mitochondria to nucleus in cardiomyocytes and is secreted into the circulation from the liver in a manner dependent on nuclear factor (erythroid‐derived 2)‐like 2, a key transcriptional regulator of the antioxidant response. Overexpression or treatment with recombinant human PHB1 enhances the antioxidant/anti‐inflammatory response and protects HL‐1 cardiomyocytes from mitochondrial dysfunction and toxicity from cytokine stress. Importantly, administration of recombinant human PHB1 blunted inflammation and restored cardiac contractility and ATP production in mice following lipopolysaccharide challenge. This cardioprotective, anti‐inflammatory effect of recombinant human PHB1 was determined to be independent of nuclear factor (erythroid‐derived 2)‐like 2, but partially dependent on PI3K/AKT signaling in the heart. Conclusions These findings reveal a previously unknown cardioprotective effect of PHB1 during sepsis, and illustrate a pro‐survival, protective role for PHB1 in the circulation. Exploitation of circulating PHB1 as a biomarker and/or therapeutic could have widespread benefit in the clinical management of sepsis and other severe inflammatory disorders.
Details
- Title: Subtitle
- Prohibitin‐1 Is a Dynamically Regulated Blood Protein With Cardioprotective Effects in Sepsis
- Creators
- Taylor A. Mattox - Department of Pharmacology & Toxicology Brody School of MedicineEast Carolina University Greenville NC.Christine Psaltis - Department of Pharmacology & Toxicology Brody School of MedicineEast Carolina University Greenville NC.Katie Weihbrecht - University of IowaJacques Robidoux - Department of Pharmacology & Toxicology Brody School of MedicineEast Carolina University Greenville NC.Brita Kilburg-Basnyat - Department of Pharmacology & Toxicology Brody School of MedicineEast Carolina University Greenville NC.Michael P Murphy - MRC Mitochondrial Biology UnitKymberly M. Gowdy - Department of Pharmacology & Toxicology Brody School of MedicineEast Carolina University Greenville NC.Ethan J. Anderson - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.10(14), pp.e019877-e019877
- DOI
- 10.1161/JAHA.120.019877
- PMID
- 34219469
- PMCID
- PMC8483490
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Language
- English
- Date published
- 07/20/2021
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics; Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology
- Record Identifier
- 9984366036302771
Metrics
31 Record Views