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In this study, we investigated the mechanisms by which zinc inactivates p38 MAPK<\/jats:styled-content> to prevent ORCH<\/jats:styled-content>.<\/jats:p>Mice (4\u2010week old) were fed either high fat diet (HFD<\/jats:styled-content>, 60% kcal fat) or normal diet (ND<\/jats:styled-content>, 10% kcal fat) containing variable amounts of zinc (deficiency, normal and supplement) for 3 and 6 months. P38 MAPK<\/jats:styled-content> siRNA<\/jats:styled-content> and the p38 MAPK<\/jats:styled-content> inhibitor SB<\/jats:styled-content>203580 were used to suppress p38 MAPK<\/jats:styled-content> activity in vitro and in vivo<\/jats:italic>, respectively. HFD<\/jats:styled-content> activated p38 MAPK<\/jats:styled-content> and increased expression of B\u2010cell lymphoma\/CLL<\/jats:styled-content> 10 (BCL<\/jats:styled-content>10) and caspase recruitment domain family member 9 (CARD<\/jats:styled-content>9). These responses were enhanced by zinc deficiency and attenuated by zinc supplement. Administration of SB<\/jats:styled-content>203580 to HFD<\/jats:styled-content> mice or specific siRNA<\/jats:styled-content> in palmitate\u2010treated cardiomyocytes eliminated the HFD<\/jats:styled-content> and zinc deficiency activation of p38 MAPK<\/jats:styled-content>, but did not significantly impact the expression of BCL<\/jats:styled-content>10 and CARD<\/jats:styled-content>9. In cultured cardiomyocytes, inhibition of BCL<\/jats:styled-content>10 expression by siRNA<\/jats:styled-content> prevented palmitate\u2010induced increased p38 MAPK<\/jats:styled-content> activation and atrial natriuretic peptide (ANP<\/jats:styled-content>) expression. In contrast, inhibition of p38 MAPK<\/jats:styled-content> prevented ANP<\/jats:styled-content> expression, but did not affect BCL<\/jats:styled-content>10 expression. Deletion of metallothionein abolished the protective effect of zinc on palmitate\u2010induced up\u2010regulation of BCL<\/jats:styled-content>10 and phospho\u2010p38 MAPK<\/jats:styled-content>. HFD<\/jats:styled-content> and zinc deficiency synergistically induce ORCH<\/jats:styled-content> by increasing oxidative stress\u2010mediated activation of BCL<\/jats:styled-content>10\/CARD<\/jats:styled-content>9\/p38 MAPK<\/jats:styled-content> signalling. Zinc supplement ameliorates ORCH<\/jats:styled-content> through activation of metallothionein to repress oxidative stress\u2010activated BCL<\/jats:styled-content>10 expression and p38 MAPK<\/jats:styled-content> activation.<\/jats:p>","DOI":"10.1111\/jcmm.13050","type":"journal-article","created":{"date-parts":[[2017,2,3]],"date-time":"2017-02-03T14:02:40Z","timestamp":1486130560000},"page":"1182-1192","source":"Crossref","is-referenced-by-count":47,"title":["Zinc rescues obesity\u2010induced cardiac hypertrophy via<\/i> stimulating metallothionein to suppress oxidative stress\u2010activated BCL<\/scp>10\/CARD<\/scp>9\/p38 MAPK<\/scp> pathway"],"prefix":"10.1111","volume":"21","author":[{"given":"Shudong","family":"Wang","sequence":"first","affiliation":[{"name":"Cardiovascular Center The First Hospital of Jilin University Changchun Jilin China"},{"name":"Department of Pediatrics Kosair Children's Hospital Research Institute University of Louisville Louisville KY 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