A20 prevents obesity-induced development of cardiac dysfunction

Obesity and an increased free fatty acid (FFA) level are tightly linked, leading to aberrant oxidative stress, inflammation, ap- optosis, and progression to cardiovascular disorders. A20 is a ubiquitin-modifying enzymethat 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 underlyingmechanisms.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 as- sociated 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.