Calcineurin regulates myocardial function during acute endotoxemia.
BACKGROUND
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).


OBJECTIVE
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.


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.
Joshi
Mandar S
MS
Center for Cardiovascular Medicine, Columbus Children's Research Institute, Ohio State University Medical Center, Columbus, OH 43210-1252, USA.
Julian
Mark W
MW
Huff
Jennifer E
JE
Bauer
John A
JA
Xia
Yong
Y
Crouser
Elliott D
ED
D000818:Animals; D065095:Calcineurin Inhibitors; D002415:Cats; D016572:Cyclosporine / Q000494:pharmacology*; D019446:Endotoxemia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D000083162:Mitochondrial Permeability Transition Pore; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D050050:Protein Carbonylation / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D065095:Calcineurin Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; C002744:3-nitrotyrosine; D014443:Tyrosine; D016572:Cyclosporine; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D016559:Tacrolimus