Obesity increases the risk of metabolic syndrome including insulin resistance, dyslipidemia, and cardiovascular disease. We demonstrated insulin resistance, cardiac hypertrophy, and cardiac inflammation in an obese mouse model induced by a high-fat diet (HFD). Caspase recruitment domain-containing protein 9 (CARD9) and B-cell lymphoma/leukemia 10 (BCL10) were upregulated, and p38 MAPK was activated in these mice. Zinc supplementation prevented these changes with upregulation of metallothionein (MT). Deletion of MT exacerbated palmitate-triggered expression of BCL10 and p38 MAPK activation and eliminated the protective benefits of zinc in palmitate-treated cardiomyocytes. Here we further investigated the mechanisms by which endogenous MT expression affects HFD-induced cardiac remodeling and the CARD9/BCL10/p38 MAPK pathway. Male MT knockout and 129S wild-type mice were assigned to receive either a normal diet or a HFD from 8-week-age for 18 weeks. MT knockout (KO) aggravated HFD-induced obesity and systemic metabolic disorder, reflected by increased body weight, perirenal white adipose tissue, and plasma cholesterol, and cardiac hypertrophy and fibrosis. Obese MT-KO mice had abundant cardiac macrophages, upregulated cardiac proinflammatory cytokines, chemokines, adhesion molecules, CARD9, and BCL10 and activated NF-κB. MT-KO exacerbated HFD-induced trace metal dyshomeostasis and oxidative stress. MT-KO combined with HFD-induced obesity synergistically promotes cardiac remodeling, possibly via trace metal dyshomeostasis-induced oxidative stress to trigger CARD9/BCL10-mediated NF-κB activation.
Keywords: CARD9; Cardiac remodeling; Inflammation; Metallothionein; Obesity cardiomyopathy.
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