Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice

School of Physical Education and Sport, University of Sao Paulo, SP, Brazil.
The Journal of Physiology (Impact Factor: 5.04). 07/2009; 587(Pt 15):3899-910. DOI: 10.1113/jphysiol.2009.173948
Source: PubMed


Cardiomyocyte hypertrophy occurs in response to a variety of physiological and pathological stimuli. While pathological hypertrophy in heart failure is usually coupled with depressed contractile function, physiological hypertrophy associates with increased contractility. In the present study, we explored whether 8 weeks of moderate intensity exercise training would lead to a cardiac anti-remodelling effect in an experimental model of heart failure associated with a deactivation of a pathological (calcineurin/NFAT, CaMKII/HDAC) or activation of a physiological (Akt–mTOR) hypertrophy signalling pathway. The cardiac dysfunction, exercise intolerance, left ventricle dilatation, increased heart weight and cardiomyocyte hypertrophy from mice lacking α2A and α2C adrenoceptors (α2A/α2CARKO mice) were associated with sympathetic hyperactivity induced heart failure. The relative contribution of Ca2+–calmodulin high-affinity (calcineurin/NFAT) and low-affinity (CaMKII/HDAC) targets to pathological hypertrophy of α2A/α2CARKO mice was verified. While nuclear calcineurin B, NFATc3 and GATA-4 translocation were significantly increased in α2A/α2CARKO mice, no changes were observed in CaMKII/HDAC activation. As expected, cyclosporine treatment decreased nuclear translocation of calcineurin/NFAT in α2A/α2CARKO mice, which was associated with improved ventricular function and a pronounced anti-remodelling effect. The Akt/mTOR signalling pathway was not activated in α2A/α2CARKO mice. Exercise training improved cardiac function and exercise capacity in α2A/α2CARKO mice and decreased heart weight and cardiomyocyte width paralleled by diminished nuclear NFATc3 and GATA-4 translocation as well as GATA-4 expression levels. When combined, these findings support the notion that deactivation of calcineurin/NFAT pathway-induced pathological hypertrophy is a preferential mechanism by which exercise training leads to the cardiac anti-remodelling effect in heart failure.

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Available from: Julio Cesar Batista Ferreira
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    • "Presently, we have demonstrated that our exercise training protocol was efficient in attenuating reduced fractional shortening, basal tachycardia and exercise intolerance as well as the cardiac myocyte hypertrophy and cardiac fibrosis. In fact, we have previously demonstrated that AET display an anti-cardiac remodeling effect in 2A/2CARKO mice associated with an attenuation in calcineurin/NFAT signaling pathway [32]. Importantly, AET conferred reduced proteinuria and increased creatinine clearance, suggesting improved renal function. "
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    ABSTRACT: Leucine supplementation potentiates the effects of aerobic exercise training (AET) on skeletal muscle; however, its potential effects associated with AET on cardiac muscle have not been clarified yet. We tested whether leucine supplementation would potentiate the anti-cardiac remodeling effect of AET in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α2A/α2CARKO). Mice were assigned to five groups: wild type mice treated with placebo and sedentary (WT, n = 11), α2A/α2CARKO treated with placebo and sedentary (KO, n = 9), α2A/α2CARKO treated with leucine and sedentary (KOL, n = 11), α2A/α2CARKO treated with placebo and AET (KOT, n = 12) or α2A/α2CARKO treated with leucine and AET (KOLT, n = 12). AET consisted of four weeks on a treadmill with 60 min sessions (six days/week, 60% of maximal speed) and administration by gavage of leucine (1.35 g/kg/day) or placebo (distilled water). The AET significantly improved exercise capacity, fractional shortening and re-established cardiomyocytes’ diameter and collagen fraction in KOT. Additionally, AET significantly prevented the proteasome hyperactivity, increased misfolded proteins and HSP27 expression. Isolated leucine supplementation displayed no effect on cardiac function and structure (KOL), however, when associated with AET (KOLT), it increased exercise tolerance to a higher degree than isolated AET (KOT) despite no additional effects on AET induced anticardiac remodeling. Our results provide evidence for the modest impact of leucine supplementation on cardiac structure and function in exercised heart failure mice. Leucine supplementation potentiated AET effects on exercise tolerance, which might be related to its recognized impact on skeletal muscle.
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    • "These data suggest that improved cardiac function associated with sustained ARB treatment may be also due to the diminished CAMKII pathway activation. We have recently reported that CAMKII pathway is hyper-activated in sympathetic hyperactivity-induced HF, and β-blocker therapy reduced its activation and re-established cardiac function (Bartholomeu et al., 2008; Oliveira et al., 2009). Since CAMKII is a well known substrate of angiotensin II receptor-activated kinases (i.e. "
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