Zinc rescues obesity-induced cardiac hypertrophy via stimulating metallothionein to suppress oxidative stress-activated BCL10/CARD9/p38 MAPK pathway.
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.
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.|Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.
Shudong
S
Wang
Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.
Junlian
J
Gu
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.|Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.
Zheng
Z
Xu
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Zhiguo
Z
Zhang
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Tao
T
Bai
Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.
Jianxiang
J
Xu
Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.
Jun
J
Cai
Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.|Autism Center, University of Louisville, Louisville, KY, USA.
Gregory
G
Barnes
Department of Hematology Disorders, The First Hospital of Jilin University, Changchun, Jilin, China.
Qiu-Ju
QJ
Liu
Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.
Jonathan H
JH
Freedman
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Yonggang
Y
Wang
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Quan
Q
Liu
Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Yang
Y
Zheng
Department of Pediatrics, Kosair Children's Hospital Research Institute, University of Louisville, Louisville, KY, USA.|Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA.|Wendy Novak Diabetes Care Center, University of Louisville, Louisville, KY, USA.
Lu
L
Cai
D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein / Q000235:genetics*; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D006332:Cardiomegaly / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000473:pathology; D059305:Diet, High-Fat; D019587:Dietary Supplements; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D008668:Metallothionein / Q000235:genetics*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015032:Zinc / Q000008:administration & dosage / Q000172:deficiency; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D007093:Imidazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D008668:Metallothionein; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc; C093642:SB 203580
BCL10; CARD9; obesity-related cardiac hypertrophy; p38 MAPK; zinc