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A20 prevents obesity-induced development of cardiac dysfunction.

A20 prevents obesity-induced development of cardiac dysfunction.
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Xu W, Wang C, Liang M, Chen L, Fu Q, Zhang F, Wang Y, Huang D, Huang K,


Xu W, Wang C, Liang M, Chen L, Fu Q, Zhang F, Wang Y, Huang D, Huang K, (click to view)

Xu W, Wang C, Liang M, Chen L, Fu Q, Zhang F, Wang Y, Huang D, Huang K,

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Journal of molecular medicine (Berlin, Germany) 2017 11 16() doi 10.1007/s00109-017-1608-3
Abstract

Obesity and an increased free fatty acid (FFA) level are tightly linked, leading to aberrant oxidative stress, inflammation, apoptosis, and progression to cardiovascular disorders. A20 is a ubiquitin-modifying enzyme that plays a significant role in the negative regulation of inflammatory response. Here, we study the role of A20 in obesity-induced heart injury and explore the underlying mechanisms. A20 expression was first increased in mouse hearts after 4 weeks of a high-fat diet (HFD) and then was gradually decreased in the following 20 weeks. Cardiac-specific supplementation with A20 via recombinant adeno-associated virus subtype 9 (rAAV9) could reverse myocardial dysfunction, hypertrophy and fibrosis in mice exposed to 24 weeks of HFD, along with reduced cardiac apoptosis and inflammation. The beneficial actions of A20 were closely associated with its ability to repress TAK1 activation and the downstream inhibition of P38, JNK1/2, and the NF-κB pathway. TAK1 over-expression could efficiently retard the above-mentioned positive effects of A20. Therefore, our data uncovered a novel function of A20 in obesity-induced heart injury and presented a therapeutic approach for the treatment of obesity-related cardiovascular disorders.

KEY MESSAGES
A20 expression is downregulated in obesity-related hearts. A20 ameliorates HFD-induced lipid accumulation, ROS, inflammation, apoptosis, hypertrophy, fibrosis, and cardiac dysfunction. A20 represses TAK1 activation and the downstream inhibition of P38, JNK1/2, and the NF-κB pathway. TAK1 overexpression retards the beneficial effects of A20.

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