Exacerbation by knocking-out metallothionein gene of obesity-induced cardiac remodeling is associated with the activation of CARD9 signaling.

Abstract

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.