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Articles in PresS, published online ahead of print July 26, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00196.2002
Submitted on March 6, 2002
Accepted on July 23, 2002
1 Medicine, New York Medical College, Valhalla, NY, USA
2 Medicine and Physiology and Biophysics, State University Of New York, Stony Brook, NY, USA
* To whom correspondence should be addressed. E-mail: michael_goligorsky{at}nymc.edu.
The accumulated ultrastructural and biochemical evidence is highly suggestive of the existence of mitochondrial nitric oxide synthase (mtNOS), where local production of nitric oxide (NO) regulates the electron transport along the respiratory chain. Here, the functional competence of mtNOS in situ in a living cell was examined using an intravital fluorescent NO indicator, 4,5-diaminofluorescein, employing a new procedure for loading it into the mitochondria to demonstrate local NO generation in undisrupted endothelial cells and in isolated mitochondria, as well as in human embryonic kidney cells (HEK) stably expressing endothelial nitric oxide synthase. Using this approach we showed that endothelial cells incubated in the presence of high concentration of D-glucose (but not L-glucose) are characterized by the reduced (42%) NO-synthetic function of mitochondria, despite the unaltered abundance of the enzyme. In parallel, mitochondrial generation of superoxide was augmented (5-fold) in endothelial cells incubated in the presence of high concentration of D-glucose. Both the NO generation and superoxide production in hyperglycemic environment could be restored to control level by treating cells with a cell-permeable superoxide dismutase mimetic. In addition, enhanced mitochondrial superoxide production could be suppressed with an inhibitor of NOS in stimulated endothelial cells. In conclusion, the data 1) provide direct evidence of mitochondrial NO production in endothelial cells, 2) demonstrate its suppression and enhanced superoxide generation in hyperglycemic environment, and 3) provide evidence that "uncoupled" mtNOS represents an important source of superoxide anions in endothelial cells incubated in high glucose-containing medium.
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