WWP1 Deficiency Alleviates Cardiac Remodeling Induced by Simulated Microgravity.

Guohui Zhong,Shukuan Ling,Junjie Pan,Wenjuan Xing,Zifan Liu,Dingsheng Zhao,Jianwei Li,Xinxin Yuan,Yingxian Li,Yinglong Zhao

doi:10.3389/fcell.2021.739944

Abstract

Cardiac muscle is extremely sensitive to changes in loading conditions; the microgravity during space flight can cause cardiac remodeling and function decline. At present, the mechanism of microgravity-induced cardiac remodeling remains to be revealed. WW domain-containing E3 ubiquitin protein ligase 1 (WWP1) is an important activator of pressure overload-induced cardiac remodeling by stabilizing disheveled segment polarity proteins 2 (DVL2) and activating the calcium-calmodulin-dependent protein kinase II (CaMKII)/histone deacetylase 4 (HDAC4)/myocyte-specific enhancer factor 2C (MEF2C) axis. However, the role of WWP1 in cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether WWP1 was also involved in the regulation of cardiac remodeling caused by microgravity. Firstly, we detected the expression of WWP1 and DVL2 in the heart from mice and monkeys after simulated microgravity using western blotting and immunohistochemistry. Secondly, WWP1 knockout (KO) and wild-type (WT) mice were subjected to tail suspension (TS) to simulate microgravity effect. We assessed the cardiac remodeling in morphology and function through a histological analysis and echocardiography. Finally, we detected the phosphorylation levels of CaMKII and HDAC4 in the hearts from WT and WWP1 KO mice after TS. The results revealed the increased expression of WWP1 and DVL2 in the hearts both from mice and monkeys after simulated microgravity. WWP1 deficiency alleviated simulated microgravity-induced cardiac atrophy and function decline. The histological analysis demonstrated WWP1 KO inhibited the decreases in the size of individual cardiomyocytes of mice after tail suspension. WWP1 KO can inhibit the activation of the DVL2/CaMKII/HDAC4 pathway in the hearts of mice induced by simulated microgravity. These results demonstrated WWP1 as a potential therapeutic target for cardiac remodeling and function decline induced by simulated microgravity.

Highlights

Our organ systems have evolved to work under 1g environment
To assess the potential role of WWP1 in cardiac remodeling induced by simulated microgravity, hearts from mice after 6 weeks of tail suspension were assessed for WWP1 expression
These results suggested that simulated microgravity increase the protein level of WWP1, which was an activator of pathological cardiac remodeling

Summary

Introduction

Our organ systems have evolved to work under 1g environment. It is not yet clear what effects will be produced by long-term exposure to low-gravity environments and how these effects will be manifested at the cellular and molecular levels (Walls et al, 2020). Long-term pressure overload leads to pathological hypertrophy and heart failure (Hill and Olson, 2008). Cardiac atrophy was a complication for prolonged microgravity during space flight, long-term bed rest, and mechanical unloading with a ventricular assist device (Levine et al, 1997; Hill and Olson, 2008; Westby et al, 2016; Ling et al, 2018). Our early researches demonstrated that simulated microgravity induced cardiac atrophy and function decline of mice and rhesus monkeys (Zhong et al, 2016; Ling et al, 2018)

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