Zinc homeostasis plays an important role in the prevention of obesity-induced cardiac inflammation, remodeling and dysfunction

Abstract

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.

Keywords: BCL10; CARD9; Obesity cardiac remodeling; P38 MAPK; Zinc deficiency; Zinc homeostasis.