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The acute effects of exercise on cardiac NOS isoforms in diabetes are not fullyunderstood. However, long-term exercise has been reported to increase NO avail-
ability in hearts of health rats [ 150 ]. In addition, low-intensity endurance training
increased myocardial eNOS expression and NO availability in type 2 diabetic Goto-
Kakizaki rat [ 141 ]. On the contrary, Kleindienst et al. [ 151 ] showed that regular
exercise reduce iNOS expression and nitro-oxidative stress in the heart of obese
diabetic mice with no effect of β3-adrenergic receptor eNOS pathway.
6.5 Effect of Exercise on Xanthine Oxidase
Xanthine oxidase plays an important role in the pathogenesis of non-diabetic car-
diac pathologies; however, its contribution to DCM is not well established [ 152 ]. It
is an extra-mitochondrial enzyme located in the cytosol of cardiomyocytes and pro-
duces H 2 O 2 and O 2 • during the metabolism of xanthine and hypoxanthine into uric
acid [ 110 ]. In dogs with induced dilated cardiomyopathy, a fourfold increase in
xanthine oxidase mRNA has been reported [ 153 ]. In this animal model, xanthine
oxidase inhibition resulted in significantly improved myocardial contractility and
performance [ 153 ]. In C57/BL6 diabetic mice, inhibition of xanthine oxidase
improved cardiac dysfunction by decreasing fibrosis and oxidative/nitrosative stress
[ 154 ]. In addition, xanthine oxidase inhibition attenuated left ventricular dysfunc-
tion in STZ-induced diabetic rats [ 155 ]. Till now, nothing in known about the effect
of exercise on xanthine oxidase in the diabetic heart. Therefore, studies investigat-
ing the effect of acute and long-term exercise on the expression and/or activity of
xanthine oxidase in DCM are required.
6.6 Effect of Exercise on 12/15 Lipoxygenase (LOX)
12-LOX and 15-LOX are members of a family of enzymes that oxidatively metabo-
lize arachidonic acid into 12- and 15-hydroxyeicosatetraenoic acids. ROS are
released during the metabolism of arachidonic acid by 12- and 15-LOX. Activation
of these enzymes has been reported to be induced by hyperglycemia and to be asso-
ciated with cardiac oxidative stress and DCM [ 110 ]. 12/15-LOX-knockout mice
with STZ-induced diabetes exhibited reduced cardiac fibrosis when compared with
the wild-type mice, suggesting the role of 12/15-LOX in DCM [ 156 ]. In addition,
deletion of 12/15-LOX in diabetic mice resulted in decreased cardiac lipid peroxi-
dation [ 156 ]. These findings suggest that 12/15-LOX inhibition may represent a
therapeutic target against DCM. As yet, no studies have investigated the effect of
exercise on 12/15-LOX in the diabetic heart.
A.M. Mahmoud