Background Prolonged breathing of nitric oxide reduces myocardial ischemia-reperfusion injury but the precise mechanisms responsible for the cardioprotective effects of inhaled nitric oxide are incompletely understood. Methods We investigated the fate of inhaled nitric oxide (80 parts per million) in mice, and quantified the formation of nitric oxide metabolites (NO-metabolites) in blood and tissues. We tested whether the accumulation of NO-metabolites correlated with the ability of inhaled nitric oxide to protect against cardiac ischemia-reperfusion injury. Results Mice absorbed nitric oxide in a nearly linear fashion (0.19±0.02 μmol/g·h). Breathing nitric oxide rapidly increased a broad spectrum of NO-metabolites. Levels of erythrocytic S-nitrosothiols, N-nitrosamines and nitrosyl-hemes exceeded nitrite within 30 sec of commencing nitric oxide inhalation. Marked increases of lung S-nitrosothiols and liver N-nitrosamines levels were measured, as well as elevated cardiac and brain NO-metabolite levels. Breathing hypoxic concentrations potentiated the ability of inhaled nitric oxide to increase cardiac NO-metabolite levels. Concentrations of each NO-metabolite, except nitrate, rapidly reached a plateau and were similar after 5 and 60 minutes. Studying a murine cardiac ischemia-reperfusion injury model, breathing nitric oxide for either 5 or 60 min before reperfusion decreased MI/AAR by 31 and 32%, respectively. Conclusions Breathing nitric oxide leads to the rapid accumulation of a variety of NO-metabolites in blood and tissues, contributing to the ability of brief periods of nitric oxide inhalation to provide cardioprotection against ischemia-reperfusion injury. The NO-metabolite concentrations achieved in a target tissue may be more important than the absolute amounts of nitric oxide absorbed.
Myeloid differentiation factor 88 (MyD88), an adaptor critical for innate immune function, plays a role in neutrophil recruitment and myocardial injury after transient ischemia. However, how MyD88 signaling modulates neutrophil function and myocardial injury remains unclear. In an in vivo model of neutrophil migration and a chimeric model of MyD88 deletion, we demonstrated that Gr-1-positive (Gr-1(+)) neutrophil migration was significantly decreased by 68% in MyD88-deficient (Myd88(-/-)) mice and by 33% in knockout→wild-type (KO→WT; donor→recipient) chimeric mice, which lacked MyD88 in bone marrow cells but maintained normal MyD88 expression in the heart. This marked attenuation in neutrophil migration was associated with decreased peritoneal neutrophil CXCR2 expression and lower peritoneal KC, a neutrophil chemoattractant, in MyD88(-/-) mice. Moreover, in vitro, KC induces significantly more downregulation of CXCR2 expression in MyD88(-/-) than WT neutrophils. In an in vivo model of myocardial ischemia-reperfusion (I/R) injury, KO→WT chimeric mice had significantly smaller infarct sizes compared with the WT→WT mice. While there was a marked increase in proinflammatory cytokine/chemokine expression in the myocardium following I/R, there was no significant difference between WT→WT and KO→WT mice. In contrast, Gr-1(+) neutrophil recruitment in the myocardium was markedly attenuated in MyD88(-/-) mice. Deletion of Toll-interleukin-1 receptor (TIR)-domain-containing adaptor protein-inducing interferon-β-mediated transcription factor (Trif), another innate immune adaptor, had no effect on the KC-mediated CXCR2 downregulation or on myocardial neutrophil recruitment after I/R. Taken together, these findings suggest that MyD88 signaling is essential for maintaining neutrophil migratory function and chemokine receptor expression. MyD88 signaling in bone marrow-derived circulating cells may play a specific and critical role in the development of myocardial I/R-induced injury.
Brown adipose tissue (BAT) has well recognized thermogenic properties mediated by uncoupling protein 1 (UCP1); more recently, BAT has been demonstrated to modulate cardiovascular risk factors. To investigate whether BAT also affects myocardial injury and remodeling, UCP1-deficient (UCP1 −/− ) mice, which have dysfunctional BAT, were subjected to catecholamineinduced cardiomyopathy. At baseline, there were no differences in echocardiographic parameters, plasma cardiac troponin I (cTnI) or myocardial fibrosis between wild-type (WT) and UCP1 −/− mice. Isoproterenol infusion increased cTnI and myocardial fibrosis and induced left ventricular (LV) hypertrophy in both WT and UCP1 −/− mice. UCP1 −/− mice also demonstrated exaggerated myocardial injury, fibrosis, and adverse remodeling, as well as decreased survival. Transplantation of WT BAT to UCP1 −/− mice prevented the isoproterenol-induced cTnI increase and improved survival, whereas UCP1 −/− BAT transplanted to either UCP1 −/− or WT mice had no effect on cTnI release. After 3 days of isoproterenol treatment, phosphorylated AKT and ERK were lower in the LV's of UCP1 −/− mice than in those of WT mice. Activation of BAT was also noted in a model of chronic ischemic cardiomyopathy, and was correlated to LV dysfunction. Deficiency in UCP1, and accompanying BAT dysfunction, increases cardiomyocyte injury and adverse LV remodeling, and decreases survival in a mouse model of catecholamine-induced cardiomyopathy. Myocardial injury and decreased survival are rescued by transplantation of functional BAT to UCP1 −/− mice,
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