Tripartite motif 10 regulates cardiac hypertrophy by targeting the PTEN/AKT pathway.

Hui Yang,Chun‐Lin Yin,Hong‐Xia Wang,Hui‐Hua Li,Xue Xiao,Cui Tian,Xiao‐Xiao Wang,Chun‐Yu Zhou

doi:10.1111/jcmm.15257

Abstract

The pathogenesis of cardiac hypertrophy is tightly associated with activation of intracellular hypertrophic signalling pathways, which leads to the synthesis of various proteins. Tripartite motif 10 (TRIM10) is an E3 ligase with important functions in protein quality control. However, its role in cardiac hypertrophy was unclear. In this study, neonatal rat cardiomyocytes (NRCMs) and TRIM10‐knockout mice were subjected to phenylephrine (PE) stimulation or transverse aortic constriction (TAC) to induce cardiac hypertrophy in vitro and in vivo, respectively. Trim10 expression was significantly increased in hypertrophied murine hearts and PE‐stimulated NRCMs. Knockdown of TRIM10 in NRCMs alleviated PE‐induced changes in the size of cardiomyocytes and hypertrophy gene expression, whereas TRIM10 overexpression aggravated these changes. These results were further verified in TRIM10‐knockout mice. Mechanistically, we found that TRIM10 knockout or knockdown decreased AKT phosphorylation. Furthermore, we found that TRIM10 knockout or knockdown increased ubiquitination of phosphatase and tensin homolog (PTEN), which negatively regulated AKT activation. The results of this study reveal the involvement of TRIM10 in pathological cardiac hypertrophy, which may occur by prompting of PTEN ubiquitination and subsequent activation of AKT signalling. Therefore, TRIM10 may be a promising target for treatment of cardiac hypertrophy.

Highlights

Sustained pathological cardiac hypertrophy, which is characterized by cell size enlargement and cardiac contractility dysfunction with subsequent interstitial fibrosis, eventually progresses to heart failure.[1,2] Extracellular stress, including biomechanical stress and neurohumoral mediators, activates intracellular hypertrophic signalling pathways, leading to an imbalance of proteins synthesis and degradation.[3,4] many studies have demonstrated the involvement of protein ubiquitination pathways in cardiac hypertrophy,[5] the molecular mechanism has not yet been fully clarified.Tripartite motif 10 (TRIM10), a member of both the tripartite motif (TRIM) family protein and E3 ubiquitin ligase complex, contains an N-terminal RING finger/B-box/coiled coil motif.[6]
We identified a novel role of TRIM10 in cardiac hypertrophy
TRIM family proteins have been demonstrated as key components involved in cardiomyocyte differentiation and apoptosis and play an important role in dilated cardiomyopathy and cardiac hypertrophy/atrophy/ ischemia.[8,20]

Summary

| INTRODUCTION

Sustained pathological cardiac hypertrophy, which is characterized by cell size enlargement and cardiac contractility dysfunction with subsequent interstitial fibrosis, eventually progresses to heart failure.[1,2] Extracellular stress, including biomechanical stress and neurohumoral mediators, activates intracellular hypertrophic signalling pathways, leading to an imbalance of proteins synthesis and degradation.[3,4] many studies have demonstrated the involvement of protein ubiquitination pathways in cardiac hypertrophy,[5] the molecular mechanism has not yet been fully clarified. TRIM10 knockdown significantly prevented phenylephrine (PE)-stimulated enlargement of cells, whereas TRIM10 overexpression aggravated this effect in vitro. This effect was confirmed following transverse aortic constriction (TAC)-induced cardiac remodelling in mice. Our results identify TRIM10 as a potential novel regulator involved in pathological cardiac hypertrophy, mainly through its action on PI3K/AKT signalling

| MATERIALS AND METHODS

| DISCUSSION