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room temperature and found that, regardless of the amount of HSP72, cardioprotec-
tion was similar between groups [ 8 , 70 , 99 ]. In addition, Starnes et al. [ 81 ] stated
that elevated myocardial HSP70 does not necessarily imply in improved protection
against myocardial dysfunction, as they observed that exercise training increased
HSP70 2.7-fold, but did not provide enhanced protection following 20 min of
ischemia. Therefore, although an increased HSP72 level may confer protection, this
does not seem to be a prerequisite for exercise-induced cardioprotection [ 20 ].
5.1 Altered Nitric Oxide Signaling
The observations that exercise cardioprotective effect lasts longer than the return of
antioxidant enzymes and HSP72 to pre-exercise levels suggested that another cyto-
protective molecule was responsible for providing protection during IRI [ 20 ]. This
conclusion has stimulated studies focused in the involvement of NO in exercise-
induced cardioprotection given that exercise induces an increase in NO that lasts for
at least 1 week after the end of training [ 100 , 101 ].
Exercise causes high vascular wall shear stress throughout the body, which inturn increases the expression and activity of eNOS [ 102 ] and iNOS [ 16 ], resulting
in an increase in NO and its metabolites (nitrate and nitrosothiols) [ 100 , 101 ]. The
exact cardioprotective effects attributed to NO and its metabolites during IRI is a
subject of much debate; however, hypothesized mechanisms include reduction in
ROS, augmented coronary flow due to increased vasodilation, inhibition of calcium
influx into myocytes, antagonism of β-adrenergic stimulation, reduction in cardiac
oxygen consumption, and actions on sarcolemmal KAT P channels through cGMP-
PKG signaling [ 23 ]. Together, these changes could protect cardiac myocytes against
IRI. Babai et al. [ 16 ], for instance, showed that exercise reduced the severity of
arrhythmias during IRI that was abolished after using a nitric oxide inhibitor.
Although evidence of the involvement of NO in the cardioprotective effect of exer-
cise accumulates in literature [ 15 , 17 , 18 ], it should be mentioned that controversial
data exist. Eventually, exercise may produce excessive NO that could react with
anion superoxide, forming peroxynitrite, which is cytotoxic [ 103 ]. In addition,
Taylor et al. [ 104 ] reported that exercise induced cardioprotection against IRI, even
when NO production was blocked. Therefore, although the putative importance of
NO signaling in providing cardioprotetion cannot be ruled out, it should be better
addressed.
5.2 Antioxidant Capacity
Imbalance between oxidation-reduction reactions and cellular antioxidant defense
mechanisms is called oxidative stress. ROS and other oxidants (including NO) are
generated as by-products and intermediates of normal cell metabolism, these
10 Cardiac Ischemia/Reperfusion Injury: The Bene cial Effects of Exercise