Abstract P236: Tripartite Motif 8 Contributes to Pathological Cardiac Hypertrophy Through Enhancing TAK1-dependent Signaling Pathways

Abstract

Tripartite motif (TRIM) 8 functions as an E3 ligase, interacting with and ubiquitinating diverse substrates, and is implicated in various pathological processes. However, the biological function of TRIM8 in the heart remains largely uncharacterized. This study aims to explore the role of TRIM8 in the development of cardiac hypertrophy and heart failure (HF). Mice and isolated neonatal rat cardiomyocytes (NRCMs) overexpressing or lacking TRIM8 were examined in several experiment. The effect of aortic banding (AB)-induced cardiac hypertrophy were analyzed by echocardiographic, pathological and molecular analyses. Our results indicated that the TRIM8 overexpression in hearts exacerbated the pathological cardiac hypertrophy triggered by AB, promoting cardiomyocytes enlargement and fibrosis formation by about 41% and 52%. In contrast, the development of pathological cardiac hypertrophy was profoundly blocked in TRIM8-deficient hearts. Mechanistically, the present study suggests that TRIM8 may elicit cardio-detrimental effects by promoting the activation of TAK1-p38/JNK signaling pathways. Similar results were observed in cultured NRCMs treated with angiotensin II. In addition, the rescue experiments using the TAK1-specific inhibitor 5z-7-ox confirmed the requirement of TAK1 activation in pressure overload-mediated pathological cardiac hypertrophy in TRIM8-overexpressing hearts. Furthermore, a physical interaction between TRIM8 and TAK1 was identified by co-immunoprecipitation experiments. Our study demonstrated that TRIM8 plays a deleterious role in pressure overload-induced cardiac hypertrophy by accelerating the activation of TAK1-dependent signaling pathways.