FBXW5 acts as a negative regulator of pathological cardiac hypertrophy by decreasing the TAK1 signaling to pro-hypertrophic members of the MAPK signaling pathway

Pathological cardiac hypertrophy is a crucial cause of cardiac morbidity and mortality worldwide. However, the molecular mechanisms of this disease remain incompletely understood. As a member of E3 ubiquitin ligases, F-box/WD repeat-containing protein 5 (FBXW5) has been implicated in various pathophysiological processes. However, the role of FBXW5 in pathological cardiac hypertrophy remains largely unknown. In this study, decreased expression of FBXW5 was observed in both neonatal rat cardiomyocytes and mouse hearts with hypertrophic remodeling. Gain- and loss-of-function experiments were performed to study the potential function of FBXW5 in pathological cardiac hypertrophy. The in vitro results showed that FBXW5 had a protective effect against cardiac hypertrophy induced by phenylephrine (PE). FBXW5 knockout mice and mice with AAV9-mediated FBXW5 overexpression were generated. Consistent with the in vitro results, FBXW5 deficiency aggravated cardiac hypertrophy induced by pressure overload. FBXW5 overexpression protected mice from hypertrophic stimuli. Remarkably, FBXW5 ameliorated pathological cardiac hypertrophy by directly interacting with the protein transforming growth factor-beta-activated kinase 1 (TAK1) and blocking the mitogen-activated protein kinase (MAPK) signaling pathway. Furthermore, inhibition of TAK1 prevented the effects of FBXW5 on agonist- or pressure overload-induced cardiac hypertrophy. These findings imply that FBXW5 is an essential negative regulator and may be a potential therapeutic target for pathological cardiac hypertrophy.