Published ahead of print on January 19, 2006, doi:10.1164/rccm.200411-1507OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200411-1507OC
Calcineurin Regulates Myocardial Function during Acute EndotoxemiaCenter for Cardiovascular Medicine, Columbus Children's Research Institute; and Division of Pulmonary, Critical Care, and Sleep Medicine, and Division of Cardiovascular Medicine, Dorothy M. Davis Heart and Lung Research Institute, Ohio State University Medical Center, Columbus, Ohio Correspondence and requests for reprints should be addressed to Elliott D. Crouser, M.D., Ohio State University Medical Center, 201F DHLRI, 473 West 12th Avenue, Columbus, OH 43210-1252. E-mail: elliott.crouser{at}osumc.edu 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.
Key Words: LPS • mitochondria • multiple organ dysfunction syndrome • nitration • sepsis This article has been cited by other articles:
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