Complexity of Inducible Nitric Oxide Synthase

Abstract

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 ␤-adrenergic stimulation of wild-type myocytes. Surprisingly, myocyte iNOS activity was essential rather than detrimental for the development of ␤-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 ␤-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.

Tadalafil Integrates Nitric Oxide-Hydrogen Sulfide Signaling to Inhibit High Glucose-induced Matrix Protein Synthesis in Podocytes

“…studies in cardiac myocytes highlight the complex role of iNOS in myocardial injury in lipopolysaccharide-induced endotoxemia. Whereas iNOS activation in the infiltrating leukocytes inhibits cardiomyocyte contraction via oxidative stress, the activity of iNOS in the cardiomyocyte is important for its adaptive increased contraction in response to adrenergic stimulation in endotoxemia (54). These data highlight the importance of context and cellular source of iNOS in assessing whether it plays an injurious or beneficial role in tissue injury.…”

Absence of Inducible Nitric Oxide Synthase Reduces Myocardial Damage During Ischemia Reperfusion in Streptozotocin-Induced Hyperglycemic Mice

“…Against this background is the observation that peroxynitrite formed after myocardial infarction is not associated with increased myocardial injury in nondiabetic animals. As pharmacological studies (29) show that peroxynitrite-neutralizing agents are protective in nondiabetic animals, it is possible to hypothesize that in nondiabetic animals, iNOS-derived NO has multiple roles, such as maintenance of vascular tone and possibly inhibition of mononuclear cell recruitment (30). These all are beneficial roles and protect against myocardial ischemia-reperfusion injury.…”

In Vivo Nitric Oxide Production and iNOS Expression in X-Ray Irradiated Mouse Skin

“…To determine the biological role of iNOS in skin, however, the cellular source of NO production should be identified. 32) The functions of iNOS are intriguing because of its contradictory effects. Recent studies imply that iNOS is associated with cell proliferation and differentiation even its functions are still controversial.…”