Abstract
Sympathetic hyperactivity induces adverse effects in myocardial. Recent studies have shown that exercise training induces cardioprotection against sympathetic overload; however, relevant mechanisms of this issue remain unclear. We analyzed whether exercise can prevent pathological hypertrophy induced by sympathetic hyperactivity with modulation of the kallikrein-kinin and angiogenesis pathways. Male Wistar rats were assigned to non-trained group that received vehicle; non-trained isoproterenol treated group (Iso, 0.3 mg kg−1 day−1); and trained group (Iso+Exe) which was subjected to sympathetic hyperactivity with isoproterenol. The Iso rats showed hypertrophy and myocardial dysfunction with reduced force development and relaxation of muscle. The isoproterenol induced severe fibrosis, apoptosis and reduced myocardial capillary. Interestingly, exercise blunted hypertrophy, myocardial dysfunction, fibrosis, apoptosis and capillary decreases. The sympathetic hyperactivity was associated with high abundance of ANF mRNA and β-MHC mRNA, which was significantly attenuated by exercise. The tissue kallikrein was augmented in the Iso+Exe group, and kinin B1 receptor mRNA was increased in the Iso group. Moreover, exercise induced an increase of kinin B2 receptor mRNA in myocardial. The myocardial content of eNOS, VEGF, VEGF receptor 2, pAkt and Bcl-2 were increased in the Iso+Exe group. Likewise, increased expression of pro-apoptotic Bad in the Iso rats was prevented by prior exercise. Our results represent the first demonstration that exercise can modulate kallikrein-kinin and angiogenesis pathways in the myocardial on sympathetic hyperactivity. These findings suggest that kallikrein-kinin and angiogenesis may have a key role in protecting the heart.
Highlights
Initial activation of cardiac sympathetic drive is observed in chronic heart failure, and it is followed by increased and generalized sympathetic stimulation [1]
It was shown that isoproterenol caused hypertrophy, necrosis, apoptosis, fibrosis, and reduced capillary size in the left ventricle (LV) [7]; interestingly, all negative effects of sympathetic hyperactivity were prevented by exercise
In a transgenic rat model harboring human tissue kallikrein, we found that isoproterenol induced less cardiac hypertrophy as indicated by reduction in markers associated with growth and fibrosis
Summary
Initial activation of cardiac sympathetic drive is observed in chronic heart failure, and it is followed by increased and generalized sympathetic stimulation [1]. Common consequences of sympathetic hyperactivity are negative effects on the heart, such as injury, hypertrophy, and dysfunction [2,3]. Exercise training exerts several positive effects on the cardiovascular system, such as improved heart function [4,5]. It was shown that isoproterenol caused hypertrophy, necrosis, apoptosis, fibrosis, and reduced capillary size in the left ventricle (LV) [7]; interestingly, all negative effects of sympathetic hyperactivity were prevented by exercise. We showed that exercise blunted isoproterenol-induced LV hypertrophy as well as improved myocardial performance. These findings were associated with inhibition of pro-inflammatory cytokines in the myocardium [8]
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