Table 1.

Selected Cytotoxic Processes Initiated by Peroxynitrite, with Potential Relevance to Diabetic Complications

Action	Mechanism(s)
Cytosolic enzyme inhibition	Oxidation, nitration
Membrane pump inhibition	Oxidation, nitration
Antioxidant enzyme inhibition	Oxidation, nitration
Signal transduction pathway disturbances	Oxidation, nitration
DNA injury	Oxidation, nitration, deamination, adduct formation
Surfactant protein damage	Nitration
Metalloproteinase activation	S-glutoxidation of prometalloproteinases
Antioxidant enzyme depletion	Glutathione, cysteine oxidation
Inhibition of BH4-dependent enzymes	Direct BH4 oxidation
Inhibition of NAD-dependent enzymes	NAD oxidation, NAD depletion via PARP
Lipid peroxidation	Peroxidation
Oxidative chain reactions	Lipid peroxidation, generation of reactive alpha-oxoaldehydes from glucose
Mitochondrial dysfunction	Inhibition of cytochromes, NADH-COQ1, etc.
Upregulation of adhesion receptors	NF- κB activation
GAPDH inhibition	Multiple, including PARP activation
Protein kinase C activation	Multiple, including GAPDH inhibition via PARP activation
Active DNA fragmentation	Caspase activation
Calcium dysregulation	Dysfunctional calcium pumps and cell energetics
Cell Necrosis	Mitochondrial injury, energetic collapse, oxidation, nitration, antioxidant depletion, calcium dysregulation
Apoptosis	Mitochondrial injury, DNA injury, caspase activation, signal transduction disturbances, calcium dysregulation

(Please note that to date many of the mechanisms listed have been demonstrated in vitro but not in experimental or clinical diabetes in vivo).