Objective

Isoproterenol (ISO) is widely used agent to study the effects of interventions which could prevent or attenuate the development of myocardial infarction. The sequence of pathological event’s revealed that increased myocardial tissue oxygen demand and energy dysregulation exist early during Iso-induced cardiac toxicity. Later, tissue hypoxia results in increased oxidative stress, inflammation and fibrosis along with cardiac dysfunction in this model. The canonical Wnt/β-catenin pathway has been reported to directly implicate in inducing cardiomyocyte hypertrophy and remodelling. However, less is known about the role of non-canonical Wnt signalling in cardiac diseases.

Method

Certain evidences have suggested that the activation of Wnt could up-regulate key energy sensor and cell growth regulator mTOR (Mechanistic target of rapamycin) by inhibition of GSK-3β mediator.

Result

The GSK-3β could negatively influence the mTOR activity and produce energy dysregulation during stress or hypoxic conditions. This suggests that the inhibition of GSK-3β by Wnt signalling could up-regulate mTOR levels and thereby restore early myocardial tissue energy balance and prevent cardiac toxicity in rodents.

Conclusion

We hereby discuss a novel therapeutic role of the β-catenin independent, Wnt–GSK3–mTOR axis in attenuation of Iso-induced cardiotoxicity in rodents.

中文翻译：

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β-连环蛋白非依赖性 Wnt-GSK3-mTOR 信号在异丙肾上腺素诱导的心脏毒性模型中调节能量代谢的演变

客观的

异丙肾上腺素 (ISO) 被广泛用于研究干预措施的效果，这些干预措施可以预防或减轻心肌梗塞的发展。病理事件的序列表明，在 Iso 诱导的心脏毒性早期存在心肌组织需氧量增加和能量失调。后来，组织缺氧导致该模型中氧化应激、炎症和纤维化以及心脏功能障碍增加。据报道，经典的 Wnt/β-catenin 通路直接涉及诱导心肌细胞肥大和重塑。然而，对非经典 Wnt 信号在心脏病中的作用知之甚少。

方法

某些证据表明，Wnt 的激活可以通过抑制 GSK-3β 介质来上调关键能量传感器和细胞生长调节剂 mTOR（雷帕霉素的机械靶点）。

结果

GSK-3β 可能会对 mTOR 活性产生负面影响，并在压力或缺氧条件下产生能量失调。这表明 Wnt 信号传导对 GSK-3β 的抑制可以上调 mTOR 水平，从而恢复早期心肌组织能量平衡并防止啮齿动物的心脏毒性。

结论

我们在此讨论了独立于 β-连环蛋白的 Wnt-GSK3-mTOR 轴在减弱 Iso 诱导的啮齿动物心脏毒性方面的新治疗作用。