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.

Novel Role for Pleckstrin Homology-Like Domain Family A, Member 3 in the Regulation of Pathological Cardiac Hypertrophy.

Background Pleckstrin homology-like domain family A, member 3 (PHLDA3), a crucial member of the PHLDA family, is involved in tumor suppression, kidney injury, liver injury, and glucose metabolism. However, the role of PHLDA3 in pathological cardiac hypertrophy and heart failure remains unclear. Methods and Results In the present study, PHLDA3 expression was downregulated in hypertrophic murine hearts and angiotensin II-treated cardiomyocytes. Next, an in vitro study suggested, by using gain- and loss-of-function approaches, that PHLDA3 attenuates Ang II exposure-induced cardiomyocyte hypertrophy. Consistent with the cell phenotype, disruption of PHLDA3 aggravated the effects of pressure overload-induced pathological cardiac hypertrophy, fibrosis, and dysfunction. In contrast, PHLDA3 overexpression resulted in an attenuated hypertrophic phenotype. Molecular analysis revealed that PHLDA3 suppressed the activation of AKT-mTOR-GSK3ß-P70S6K signaling in response to hypertrophic stress, and the blockage of AKT activation rescued these adverse pathological effects of PHLDA3 deficiency-induced by AB and Ang II, respectively, in vivo and in vitro. Conclusions Collectively, our data indicated that PHLDA3 could ameliorate pressure overload-induced cardiac remodeling mainly by blocking the AKT signaling pathway, suggesting that PHLDA3 may represent a therapeutic target for the treatment of pathological cardiac hypertrophy and heart failure.