In this study, we investigated the effect of the
xanthine oxidase (XO) inhibitor,
allopurinol (ALP), on cardiac dysfunction, oxidative-nitrosative stress, apoptosis,
poly(ADP-ribose) polymerase (PARP) activity and
fibrosis associated with
diabetic cardiomyopathy in mice. Diabetes was induced in C57/BL6 mice by injection of
streptozotocin. Control and diabetic animals were treated with ALP or placebo. Left ventricular systolic and diastolic functions were measured by pressure-volume system 10 weeks after established diabetes. Myocardial XO, p22(
phox),
p40(phox), p47(
phox), gp91(
phox), iNOS, eNOS
mRNA and/or
protein levels, ROS and
nitrotyrosine (NT) formation, caspase3/7 and PARP activity,
chromatin fragmentation and various markers of
fibrosis (
collagen-1,
TGF-beta, CTGF,
fibronectin) were measured using molecular biology and biochemistry methods or immunohistochemistry. Diabetes was characterized by increased myocardial, liver and serum XO activity (but not expression), increased myocardial ROS generation, p22(
phox),
p40(phox), p47(
phox), p91(
phox)
mRNA expression, iNOS (but not eNOS) expression, NT generation,
caspase 3/7 and PARP activity/expression,
chromatin fragmentation and
fibrosis (enhanced accumulation of
collagen,
TGF-beta, CTGF and
fibronectin), and declined systolic and diastolic myocardial performance. ALP attenuated the diabetes-induced increased myocardial, liver and serum XO activity, myocardial ROS, NT generation, iNOS expression, apoptosis, PARP activity and
fibrosis, which were accompanied by improved systolic (measured by the evaluation of both load-dependent and independent indices of myocardial contractility) and diastolic performance of the hearts of treated diabetic animals. Thus, XO inhibition with ALP improves
type 1 diabetes-induced cardiac dysfunction by decreasing oxidative/nitrosative stress and
fibrosis, which may have important clinical implications for the treatment and prevention of
diabetic cardiomyopathy and vascular dysfunction.