Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway.

Abstract

Obesity often leads to obesity-related cardiac hypertrophy (ORCH), which is suppressed by zinc-induced inactivation of p38 mitogen-activated protein kinase (p38 MAPK). In this study, we investigated the mechanisms by which zinc inactivates p38 MAPK to prevent ORCH. Mice (4-week old) were fed either high fat diet (HFD, 60% kcal fat) or normal diet (ND, 10% kcal fat) containing variable amounts of zinc (deficiency, normal and supplement) for 3 and 6 months. P38 MAPK siRNA and the p38 MAPK inhibitor SB203580 were used to suppress p38 MAPK activity in vitro and in vivo, respectively. HFD activated p38 MAPK and increased expression of B-cell lymphoma/CLL 10 (BCL10) and caspase recruitment domain family member 9 (CARD9). These responses were enhanced by zinc deficiency and attenuated by zinc supplement. Administration of SB203580 to HFD mice or specific siRNA in palmitate-treated cardiomyocytes eliminated the HFD and zinc deficiency activation of p38 MAPK, but did not significantly impact the expression of BCL10 and CARD9. In cultured cardiomyocytes, inhibition of BCL10 expression by siRNA prevented palmitate-induced increased p38 MAPK activation and atrial natriuretic peptide (ANP) expression. In contrast, inhibition of p38 MAPK prevented ANP expression, but did not affect BCL10 expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate-induced up-regulation of BCL10 and phospho-p38 MAPK. HFD and zinc deficiency synergistically induce ORCH by increasing oxidative stress-mediated activation of BCL10/CARD9/p38 MAPK signalling. Zinc supplement ameliorates ORCH through activation of metallothionein to repress oxidative stress-activated BCL10 expression and p38 MAPK activation.

• Authors: Shudong Wang, Junlian Gu, Zheng Xu, Zhiguo Zhang, Tao Bai, Jianxiang Xu, Jun Cai, Gregory Barnes, Qiu-Ju Liu, Jonathan H Freedman, Yonggang Wang, Quan Liu, Yang Zheng, Lu Cai
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 6 Pg. 1182-1192 (06 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28158919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• B-Cell CLL-Lymphoma 10 Protein
• Bcl10 protein, mouse
• CARD Signaling Adaptor Proteins
• Card9 protein, mouse
• Imidazoles
• Pyridines
• RNA, Small Interfering
• Metallothionein
• p38 Mitogen-Activated Protein Kinases
• Zinc
• SB 203580

Topics

• Animals
• B-Cell CLL-Lymphoma 10 Protein (genetics)
• CARD Signaling Adaptor Proteins (genetics)
• Cardiomegaly (drug therapy, etiology, genetics, pathology)
• Diet, High-Fat
• Dietary Supplements
• Gene Expression Regulation (drug effects)
• Humans
• Imidazoles (administration & dosage)
• Metallothionein (genetics)
• Mice
• Myocytes, Cardiac (drug effects)
• Obesity (complications, genetics, pathology)
• Oxidative Stress (drug effects)
• Pyridines (administration & dosage)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects)
• Zinc (administration & dosage, deficiency)
• p38 Mitogen-Activated Protein Kinases (genetics)