Pediatric Research Institute, Departments of Pediatric, University of Louisville School of Medicine, Louisville, KY, USA; Center of Cardiovascular Disorders, the First Hospital of Jilin University, Changchun, Jilin, China.
Pediatric Research Institute, Departments of Pediatric, University of Louisville School of Medicine, Louisville, KY, USA; Departments of Radiation Oncology, Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA.
J Trace Elem Med Biol. 2020 Dec;62:126615. doi: 10.1016/j.jtemb.2020.126615. Epub 2020 Jul 10.
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.
肥胖症常导致心血管疾病，如肥胖相关性心肌肥厚（ORCH），这是由于慢性心脏炎症所致。锌对于许多转录因子的结构和功能至关重要，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，其在肥胖相关心脏发病机制中的作用及其潜在的潜在机制尚不清楚。本综述旨在总结锌稳态在预防 ORCH 中的作用的现有证据。最近有报道称，当给四周大的小鼠喂食高脂肪饮食（HFD）或正常饮食（含锌不足、适量或补充锌）时，HFD 会引起肥胖和 ORCH，同时 p38 MAPK 磷酸化增加，B 细胞淋巴瘤/白血病 10（BCL10）和半胱天冬酶募集结构域家族成员 9（CARD9）的表达增加。锌缺乏进一步加重了这些影响，而锌补充则显著缓解了这些影响。机制上，在 HFD 喂养的小鼠中给予 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/肥胖引起的心肌肥大和炎症。在培养的心肌细胞中，siRNA 抑制 BCL10 的表达可防止软脂酸诱导的 p38 MAPK 激活和心钠肽表达增加。金属硫蛋白缺失消除了锌对软脂酸诱导的 BCL10 和磷酸化 p38 MAPK 上调的保护作用。结合其他最近的研究，我们得出结论，HFD 和锌缺乏通过增加氧化应激介导的 BCL10/CARD9/p38 MAPK 信号通路的激活协同诱导 ORCH。锌补充通过激活金属硫蛋白来改善 ORCH，以抑制氧化应激激活的 BCL10 表达和 p38 MAPK 激活。
