Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice
Cardiac anti-remodelling effect of aerobic training is associated with a reduction in the calcineurin/NFAT signalling pathway in heart failure mice
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DOI：
10.1113/jphysiol.2009.173948
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发表时间：
2009-08-01
影响因子：
5.5
通讯作者：
Brum, P. C.
中科院分区：
文献类型：
--
作者：
Oliveira, R. S. F.;Ferreira, J. C. B.;Brum, P. C.
心肌细胞肥大是对多种生理和病理刺激的反应而发生的。心力衰竭中的病理性肥大通常与收缩功能下降相关，而生理性肥大则与收缩性增加相关。在本研究中，我们探讨了在与病理性（钙调神经磷酸酶/NFAT、CaMKII/HDAC）失活或生理性（Akt-mTOR）肥大信号通路激活相关的心力衰竭实验模型中，8周的中等强度运动训练是否会产生心脏抗重塑作用。缺乏α(2A)和α(2C)肾上腺素受体的小鼠(α(2A)/α(2C)ARKO小鼠)的心功能不全、运动不耐受、左心室扩张、心脏重量增加和心肌细胞肥大与交感神经过度活跃引起的心力衰竭有关。 Ca2+-钙调蛋白高亲和力（钙调神经磷酸酶/NFAT）和低亲和力（CaMKII/HDAC）靶点对α(2A)/α(2C)ARKO小鼠病理性肥大的相对贡献得到验证。虽然α(2A)/α(2C)ARKO小鼠中核钙调神经磷酸酶B、NFATc3和GATA-4易位显着增加，但CaMKII/HDAC激活没有观察到变化。正如预期的那样，环孢素治疗减少了 α(2A)/α(2C)ARKO 小鼠中钙调神经磷酸酶/NFAT 的核转位，这与改善心室功能和显着的抗重塑作用有关。 Akt/mTOR 信号通路在 alpha(2A)/alpha(2C)ARKO 小鼠中未激活。运动训练改善了 α(2A)/α(2C)ARKO 小鼠的心脏功能和运动能力，并降低了心脏重量和心肌细胞宽度，同时减少了核 NFATc3 和 GATA-4 易位以及 GATA-4 表达水平。综合起来，这些发现支持了以下观点：钙调神经磷酸酶/NFAT 通路诱导的病理性肥大的失活是运动训练导致心力衰竭中心脏抗重塑作用的优先机制。
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 alpha(2A) and alpha(2C) adrenoceptors (alpha(2A)/alpha(2C)ARKO 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 alpha(2A)/alpha(2C)ARKO mice was verified. While nuclear calcineurin B, NFATc3 and GATA-4 translocation were significantly increased in alpha(2A)/alpha(2C)ARKO mice, no changes were observed in CaMKII/HDAC activation. As expected, cyclosporine treatment decreased nuclear translocation of calcineurin/NFAT in alpha(2A)/alpha(2C)ARKO mice, which was associated with improved ventricular function and a pronounced anti-remodelling effect. The Akt/mTOR signalling pathway was not activated in alpha(2A)/alpha(2C)ARKO mice. Exercise training improved cardiac function and exercise capacity in alpha(2A)/alpha(2C)ARKO 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.