Document Detail


Calcineurin regulates myocardial function during acute endotoxemia.
MedLine Citation:
PMID:  16424445     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Cyclosporin A (CsA) is known to preserve cardiac contractile function during endotoxemia, but the mechanism is unclear. Increased nitric oxide (NO) production and altered mitochondrial function are implicated as mechanisms contributing to sepsis-induced cardiac dysfunction, and CsA has the capacity to reduce NO production and inhibit mitochondrial dysfunction relating to the mitochondrial permeability transition (MPT).
OBJECTIVES: We hypothesized that CsA would protect against endotoxin-mediated cardiac contractile dysfunction by attenuating NO production and preserving mitochondrial function.
METHODS: Left ventricular function was measured continuously over 4 h in cats assigned as follows: control animals (n = 7); LPS alone (3 mg/kg, n = 8); and CsA (6 mg/kg, n = 7), a calcineurin inhibitor that blocks the MPT, or tacrolimus (FK506, 0.1 mg/kg, n = 7), a calcineurin inhibitor lacking MPT activity, followed in 30 min by LPS. Myocardial tissue was then analyzed for NO synthase-2 expression, tissue nitration, protein carbonylation, and mitochondrial morphology and function.
MEASUREMENTS AND MAIN RESULTS: LPS treatment resulted in impaired left ventricular contractility, altered mitochondrial morphology and function, and increased protein nitration. As hypothesized, CsA pretreatment normalized cardiac performance and mitochondrial respiration and reduced myocardial protein nitration. Unexpectedly, FK506 pretreatment had similar effects, normalizing both cardiac and mitochondrial parameters. However, CsA and FK506 pretreatments markedly increased protein carbonylation in the myocardium despite elevated manganese superoxide dismutase activity during endotoxemia.
CONCLUSIONS: Our data indicate that calcineurin is a critical regulator of mitochondrial respiration, tissue nitration, protein carbonylation, and contractile function in the heart during acute endotoxemia.
Authors:
Mandar S Joshi; Mark W Julian; Jennifer E Huff; John A Bauer; Yong Xia; Elliott D Crouser
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-01-19
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  173     ISSN:  1073-449X     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2006 May 
Date Detail:
Created Date:  2006-04-24     Completed Date:  2006-06-22     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  999-1007     Citation Subset:  AIM; IM    
Affiliation:
Center for Cardiovascular Medicine, Columbus Children's Research Institute, Ohio State University Medical Center, Columbus, OH 43210-1252, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcineurin / antagonists & inhibitors*
Cats
Cyclosporine / pharmacology*
Endotoxemia / enzymology,  pathology,  physiopathology*
Mitochondria, Heart / drug effects,  pathology
Mitochondrial Membrane Transport Proteins / antagonists & inhibitors*
Myocardial Contraction / drug effects*
Myocardium / enzymology,  pathology
Nitric Oxide Synthase Type II / metabolism
Peroxidase / metabolism
Protein Carbonylation / drug effects
Superoxide Dismutase / metabolism
Tacrolimus / pharmacology*
Tyrosine / analogs & derivatives,  metabolism
Grant Support
ID/Acronym/Agency:
HL04335/HL/NHLBI NIH HHS; HL59791/HL/NHLBI NIH HHS; HL63067/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Mitochondrial Membrane Transport Proteins; 0/mitochondrial permeability transition pore; 109581-93-3/Tacrolimus; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; 59865-13-3/Cyclosporine; EC 1.11.1.7/Peroxidase; EC 1.14.13.39/Nitric Oxide Synthase Type II; EC 1.15.1.1/Superoxide Dismutase; EC 3.1.3.16/Calcineurin
Comments/Corrections

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