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As mentioned above there is circumstantial evidence that nitrosative stress and peroxynitrite formation importantly contribute to the pathogenesis of diabetic cardiomyopathy both in animals and humans. We have tested a novel metalloporphyrin peroxynitrite decomposition catalyst, FP15, in murine models of diabetic cardiovascular complications (92). We hypothesized that neutralization ofperoxynitrite with FP15 would ameliorate the development of cardiovascular dysfunction in a STZ-induced murine model of diabetes. To ensure that the animals received the FP15 treatment at a time when islet cell destruction was already complete and hyperglycemia has stabilized the treatment was initiated 6 weeks after the injection of STZ. Although FP15 did not affect blood glucose levels, it provided a marked protection against the loss of endothelium-depen-dent relaxant ability of the blood vessels (Fig. 1A) and improved the depression of both diastolic (Fig. 1B) and systolic function of the heart (92). The mechanism by which FP15 protects diabetic hearts from dysfunction may involve protection against vascular and myocardial tyrosine nitration, PARP activation, lipid peroxidation, and multiple other mechanisms, as all these mechanisms have previously been linked to diabetic cardiomyopathy and to peroxynitrite-induced cardiac injury. Additional mechanisms of peroxynitrite-mediated diabetic cardiac dysfunction may include inhibition of myofibrillar creatine kinase (93) and of succinyl-coenzyme A (CoA):3-oxoacid CoA-transferase (94) or activation of metalloproteinases (95).

There are many pathophysiological conditions of the heart that are associated with peroxynitrite formation, including acute MI, chronic ischemic heart failure, doxorubicin-induced and diabetic cardiomyopathy (93,94,96-98). It appears that peroxynitrite decomposition catalysts improve cardiac function and overall outcome in these models. For instance, FP15 reduced myocardial necrosis in our current rat model of acute MI (95) and in a recent porcine study (98). Furthermore, FP15 significantly improved cardiac function in a doxorubicin-induced model of heart failure (95). These observations—coupled with the recently reported protective effect of FP15 against diabetic cardiomyopathy— support the concept that peroxynitrite is a major mediator of myocardial injury in various pathophysiological conditions, and its effective neutralization can be of significant therapeutic benefit.

Fig. 1. (A) Reversal of diabetes-induced endothelial dysfunction by FP15 in vascular rings from STZ-diabetic mice. Acetylcholine (Ach) induced endothelium-dependent relaxation is impaired in rings from diabetic mice, which is markedly improved by FP15 treatment. Each point of the curve represents the mean ± SEM of five to seven pairs of experiments in vascular rings. *p < 0.05 in FP15-treated diabetic mice vs vehicle-treated diabetic mice. (B) Reversal of streptozotocin-evoked diabetes-induced diastolic cardiac dysfunction by FP15 in mice. Effect of diabetes (9-10 weeks) and FP15 treatment in diabetic mice on left ventricular end diastolic pressure (LVEDP) and left ventricular -dp/dt (LV -dp/dt). Results are mean ± SEM of seven experiments in each group. *p < 0.05 diabetic animals vs control; #p < 0.05 in FP15-treated diabetic mice vs vehicle-treated diabetic mice. (Reproduced with permission from ref. 92.)

Fig. 1. (A) Reversal of diabetes-induced endothelial dysfunction by FP15 in vascular rings from STZ-diabetic mice. Acetylcholine (Ach) induced endothelium-dependent relaxation is impaired in rings from diabetic mice, which is markedly improved by FP15 treatment. Each point of the curve represents the mean ± SEM of five to seven pairs of experiments in vascular rings. *p < 0.05 in FP15-treated diabetic mice vs vehicle-treated diabetic mice. (B) Reversal of streptozotocin-evoked diabetes-induced diastolic cardiac dysfunction by FP15 in mice. Effect of diabetes (9-10 weeks) and FP15 treatment in diabetic mice on left ventricular end diastolic pressure (LVEDP) and left ventricular -dp/dt (LV -dp/dt). Results are mean ± SEM of seven experiments in each group. *p < 0.05 diabetic animals vs control; #p < 0.05 in FP15-treated diabetic mice vs vehicle-treated diabetic mice. (Reproduced with permission from ref. 92.)

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