Published online before print August 18, 2003, doi: 10.1161/01.CIR.0000086321.04702.AC
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(Circulation. 2003;108:1107.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Complexity of Inducible Nitric Oxide Synthase
Cellular Source Determines Benefit Versus Toxicity
From the Department of Physiology and Biophysics, Cardiovascular (B.Y.P.) and Immunology Research Groups, University of Calgary, Alberta, Canada.
Correspondence to Dr Paul Kubes, Immunology Research Group, University of Calgary, Alberta, Canada, T2N-4N1. E-mail pkubes{at}ucalgary.ca
Received September 30, 2002; de novo received February 13, 2003; revision received April 24, 2003; accepted April 25, 2003.
Background— Inducible nitric oxide synthase (iNOS) has been shown to have both beneficial and detrimental effects in sepsis. We focused on a single organ, the heart, and used 2 distinct cell types that express iNOS—the cardiac myocyte and the infiltrating neutrophil—to study the distinct functional effects of iNOS derived from heterogeneous cellular sources.
Methods and Results— In the first series of experiments, extravascular neutrophils were exposed to isolated single endotoxemic cardiac myocytes. Adhesion of wild-type neutrophils caused a rapid decrease in myocyte shortening and a concomitant increase in neutrophil-derived intracellular oxidative stress within the myocytes that was not observed with neutrophils from iNOS-deficient animals. We previously demonstrated that neutrophil-derived superoxide was essential for myocyte dysfunction; however, superoxide production was not compromised in the iNOS-deficient neutrophils. Because both superoxide and NO were essential for the neutrophil dysfunction, we probed for but could not detect any peroxynitrite assessed by detection of nitrotyrosine. There was a significant increase in length shortening in response to ß-adrenergic stimulation of wild-type myocytes. Surprisingly, myocyte iNOS activity was essential rather than detrimental for the development of ß-adrenergic receptor–mediated increases in shortening in endotoxemic iNOS-deficient myocytes.
Conclusions— These results demonstrate that iNOS, when expressed in isolated cardiac myocytes, can regulate the response to ß-adrenergic stimulation during sepsis. However, as the neutrophils migrate in proximity to myocytes, iNOS now becomes essential for the ability of neutrophils to damage myocytes. These findings demonstrate that cellular source strongly modulates the beneficial and detrimental effect of iNOS.
Key Words: nitric oxide • myocytes • inflammation • leukocytes
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