Obesity often leads to cardiovascular diseases, such as obesity-related cardiac hypertrophy (ORCH), due to chronic cardiac inflammation. Zinc is structurally and functionally essential for many transcription factors, therefore it not only has anti-inflammatory and anti-oxidative stress functions, but also has insulin-like function, however, its role in the development of obesity-associated cardiac pathogenesis and the potentially underlying mechanism(s) remains unclear. This review aims to summarize the available evidence on the role of zinc homeostasis in the prevention of ORCH. It was recently reported that when four-week old mice were fed either high fat diet (HFD) or normal diet containing deficient, adequate or supplemented zinc, HFD induced obesity and ORCH along with increased phosphorylation of p38 MAPK and increased expression of B-cell lymphoma/ leukemia 10 (BCL10) and caspase recruitment domain family member 9 (CARD9). These effects were further aggravated by zinc deficiency and significantly alleviated by zinc supplementation. Mechanistically administration of a p38 MAPK specific inhibitor in HFD-fed mice for 3 months did not affect HFD-induced obesity and increased expression of BCL10 and CARD9, but completely abolished HFD/obesity-induced cardiac hypertrophy and inflammation. In cultured cardiomyocytes, inhibition of BCL10 expression by siRNA prevented palmitate-induced increased p38 MAPK activation and atrial natriuretic peptide expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate-induced up-regulation of BCL10 and phospho-p38 MAPK. Taken together with other recent studies, we concluded that HFD and zinc deficiency synergistically induce ORCH by increasing oxidative stress-mediated activation of BCL10/CARD9/p38 MAPK signaling. Zinc supplementation ameliorates ORCH through activation of metallothionein to repress oxidative stress-activated BCL10 expression and p38 MAPK activation.

由于慢性心脏炎症，肥胖通常会导致心血管疾病，例如与肥胖相关的心脏肥大 (ORCH)。锌在结构和功能上对许多转录因子都是必不可少的，因此它不仅具有抗炎和抗氧化应激功能，还具有胰岛素样功能，然而，它在肥胖相关心脏病发病机制的发展中的作用和潜在的潜在机制仍不清楚。本综述旨在总结关于锌稳态在预防 ORCH 中作用的现有证据。最近有报道称，当给 4 周大的小鼠喂食高脂肪饮食 (HFD) 或含有缺乏、充足或补充锌的正常饮食时，HFD 诱导肥胖和 ORCH，同时增加 p38 MAPK 的磷酸化和 B 细胞淋巴瘤/白血病 10 (BCL10) 和半胱天冬酶募集域家族成员 9 (CARD9) 的表达增加。这些影响因缺锌而进一步加重，并因补锌而显着减轻。在 HFD 喂养的小鼠中机械施用 p38 MAPK 特异性抑制剂 3 个月不会影响 HFD 诱导的肥胖和 BCL10 和 CARD9 的表达增加，但完全消除了 HFD/肥胖诱导的心脏肥大和炎症。在培养的心肌细胞中，siRNA 对 BCL10 表达的抑制阻止了棕榈酸酯诱导的 p38 MAPK 激活和心房利钠肽表达增加。金属硫蛋白的缺失消除了锌对棕榈酸诱导的 BCL10 和磷酸化 p38 MAPK 上调的保护作用。结合最近的其他研究，我们得出结论，HFD 和缺锌可通过增加氧化应激介导的 BCL10/CARD9/p38 MAPK 信号传导激活来协同诱导 ORCH。锌补充剂通过激活金属硫蛋白来抑制氧化应激激活的 BCL10 表达和 p38 MAPK 激活来改善 ORCH。