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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Zinc rescue of Akt2 gene deletion-linked murine cardiac dysfunction and pathological changes is metallothionein-dependent
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Zinc rescue of Akt2 gene deletion-linked murine cardiac dysfunction and pathological changes is metallothionein-dependent

机译：锌对Akt2基因缺失相关的小鼠心脏功能障碍和病理改变的营救是依赖金属硫蛋白的

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We have demonstrated that zinc supplementation provides cardiac protection from diabetes in mice, but its underlying mechanism remains unclear. Since zinc mimics the function of insulin, it may provide benefit to the heart via stimulating Akt-mediated glucose metabolism. Akt2 plays an important role in cardiac glucose metabolism and mice with Akt2 gene deletion (Alct2-K0) exhibit a type 2 diabetes phenotype; therefore, we assumed that no cardiac protection by zinc supplementation from diabetes would be observed in Akt2-KO mice. Surprisingly, despite Akt2 gene deletion, zinc supplementation provided protection against cardiac dysfunction and other pathological changes in Akt2-KO mice, which were accompanied by significant decreases in Akt and GSK-3beta phosphorylation. Correspondingly, glycogen synthase phosphorylation and hexokinase II and PGC-lalpha expression, all involved in the regulation of glucose metabolism, were significantly altered in diabetic hearts, along with a significantly increased expression of Akt negative regulators: PTEN, PTP1B, and TRB3. All these molecular, pathological, and functional changes were significantly prevented by 3-month zinc supplementation. Furthermore, the stimulation of Akt-mediated glucose metabolic kinases or enzymes by zinc treatment was metallothionein-dependent since it could not be observed in metallothionein-knockout mice. These results suggest that zinc preserves cardiac function and structure in Akt2-KO mice presumably due to its insulin mimetic effect on cardiac glucose-metabolism. The cardioprotective effects of zinc are metallothionein-dependent. This is very important since zinc supplementation may be required for patients with Akt2 gene deficiency or insulin resistance.
机译：我们已经证明锌补充剂可为小鼠提供心脏保护，使其免受糖尿病的侵害，但其潜在机制仍不清楚。由于锌模拟胰岛素的功能，因此可以通过刺激Akt介导的葡萄糖代谢为心脏提供益处。 Akt2在心脏葡萄糖代谢中起重要作用，具有Akt2基因缺失（Alct2-K0）的小鼠表现出2型糖尿病表型。因此，我们假设在Akt2-KO小鼠中未观察到通过补充锌补充糖尿病引起的心脏保护。出人意料的是，尽管缺失了Akt2基因，但补锌为Akt2-KO小鼠的心脏功能障碍和其他病理变化提供了保护，这些疾病伴随Akt和GSK-3beta磷酸化的显着降低。相应地，在糖尿病心脏中，均参与糖代谢调节的糖原合酶磷酸化，己糖激酶II和PGC-1α表达显着改变，同时Akt负调节剂：PTEN，PTP1B和TRB3的表达也明显增加。所有这些分子，病理学和功能的变化都可以通过3个月的锌补充来显着预防。此外，锌处理对Akt介导的葡萄糖代谢激酶或酶的刺激是金属硫蛋白依赖性的，因为在金属硫蛋白敲除小鼠中无法观察到。这些结果表明，锌可能在Akt2-KO小鼠中保留了心脏功能和结构，这归因于其胰岛素模拟对心脏葡萄糖代谢的影响。锌的心脏保护作用是金属硫蛋白依赖性的。这非常重要，因为Akt2基因缺乏或胰岛素抵抗的患者可能需要补充锌。

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