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modulates multiple redox-sensitive proteins and signaling pathways [ 131 ]. The

interaction between cytochrome b558 and the cytosolic components of NADPH

oxidase generates O 2 • through catalyzing the transfer of electrons to molecular oxy-

gen [ 110 ] (Fig. 12.3). Therefore, increased expression and activation of NOXs have

been reported in animal models of type 1 and type 2 DM [ 114 , 132 ] and were asso-

ciated with the pathogenesis of diabetes-associated vascular disease [ 133 ]. In this

context, rats with left ventricular hypertrophy (LVH) [ 134 ] and human diabetic

patients with cardiomyopathy [ 135 ] showed increased activity and expression of

NOXs. In guinea pig with LVH, NOX-dependent O 2 • production and expression of

NOX2 were significantly increased in the cardiomyocytes [ 136 ]. Overexpression of

NOX4 increased O 2 • generation, cardiac dysfunction and apoptosis of cardiac cells

[ 137 ]. Recently, Sharma et al. [ 138 ] demonstrated that STZ-induced diabetes in rats

significantly increased left ventricular p47phox and p67phox both mRNA and pro-

tein expression.

Studies on the genetic and pharmacological inhibition of NOXs have further

highlighted the role of these ROS-generating enzymes in mediating cardiomyopa-

thy. In type 1 diabetic mice, the inhibition of NOX2 reduced myocardial fibrosis and

improved cardiac function [ 139 ]. Treatment of type 2 diabetic rodents with angio-

tensin receptor blocker reduced NOX2 expression, ROS production and fibrosis of

cardiomyocytes [ 114 , 132 ]. Specific deletion of rac1, a cytosolic component of

many NOX isoforms, in cardiomyocytes significantly reduced hyperglycemia-

induced myocardial dysfunction, up-regulation of NADPH oxidase activity, ROS

generation and cardiomyocyte apoptosis [ 140 ]. The hyperglycemic db/db mice

exhibited marked inhibition of cardiomyocyte NADPH oxidase activity and apopto-

sis following treatment with a rac1 inhibitor [ 140 ]. Collectively, these data show the

critical contribution of NADPH oxidase-dependent ROS production in DCM.

The effect of exercise training on the expression and activity of NADPH oxidase

in the diabetic myocardium has been demonstrated in several studies. Grijalva et al.

[ 141 ] reported a significant reduction in NOX2 activity in the myocardium of type

Fig. 12.3 Components of NADPH oxidase

A.M. Mahmoud