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.

Microgravity prominently affected cardiovascular health, which was the gravity-dependent physical factor. Deep space exploration had been increasing in frequency, but heart function was susceptible to conspicuous damage and cardiac mass declined in weightlessness. Understanding of the etiology of cardiac atrophy exposed to microgravity currently remains limited. The 3′-untranslated region (UTR) of casein kinase-2 interacting protein-1 (Ckip-1) was a pivotal mediator in pressure overload-induced cardiac remodeling. However, the role of Ckip-1 3′-UTR in the heart during microgravity was unknown. We analyzed Ckip-1 mRNA 3′-UTR and coding sequence (CDS) expression levels in ground-based analogs such as mice hindlimb unloading (HU) and rhesus monkey head-down bed rest model. Ckip-1 3′-UTR had transcribed levels in the opposite change trend with cognate CDS expression in the hearts. We then subjected wild-type (WT) mice and cardiac-specific Ckip-1 3′-UTR-overexpressing mice to hindlimb unloading for 28 days. Our results uncovered that Ckip-1 3′-UTR remarkably attenuated cardiac dysfunction and mass loss in simulated microgravity environments. Mechanistically, Ckip-1 3′-UTR inhibited lipid accumulation and elevated fatty acid oxidation-related gene expression in the hearts through targeting calcium/calmodulin-dependent kinase 2 (CaMKK2) and activation of the AMPK-PPARα-CPT1b signaling pathway. These findings demonstrated Ckip-1 3′-UTR was an important regulator in atrophic heart growth after simulated microgravity.