WWP1 Deficiency Alleviates Cardiac Remodeling Induced by Simulated Microgravity

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

doi:10.3389/fcell.2021.739944

WWP1 Deficiency Alleviates Cardiac Remodeling Induced by Simulated Microgravity

Front Cell Dev Biol. 2021 Oct 18:9:739944. doi: 10.3389/fcell.2021.739944. eCollection 2021.

Authors

Guohui Zhong^{1

2}, Dingsheng Zhao², Jianwei Li², Zifan Liu³, Junjie Pan⁴, Xinxin Yuan², Wenjuan Xing^{1

2}, Yinglong Zhao⁵, Shukuan Ling², Yingxian Li^{1

2}

Affiliations

¹ The Key Laboratory of Aerospace Medicine, Ministry of Education, Fourth Military Medical University, Xi'an, China.
² State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China.
³ Department of Cardiovascular Medicine, Chinese PLA General Hospital & Chinese PLA Medical School, Beijing, China.
⁴ Medical College of Soochow University, Soochow University, Suzhou, China.
⁵ Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Sciences, Hebei Normal University, Shijiazhuang, China.

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.

Keywords: DVL2; HDAC4; WWP1; cardiac remodeling; simulated microgravity.