Abstract
Human cardiovascular system has adapted to Earth's gravity of 1G. The microgravity during space flight can induce cardiac remodeling and decline of cardiac function. At present, the mechanism of cardiac remodeling induced by microgravity remains to be disclosed. Casein kinase-2 interacting protein-1 (CKIP-1) is an important inhibitor of pressure-overload induced cardiac remodeling by decreasing the phosphorylation level of HDAC4. However, the role of CKIP-1 in the cardiac remodeling induced by microgravity is unknown. The purpose of this study was to determine whether CKIP-1 was also involved in the regulation of cardiac remodeling induced by microgravity. We first detected the expression of CKIP-1 in the heart from mice and monkey after simulated microgravity using Q-PCR and western blotting. Then, myocardial specific CKIP-1 transgenic (TG) and wild type mice were hindlimb-suspended (HU) to simulate microgravity effect. We estimated the cardiac remodeling in morphology and function by histological analysis and echocardiography. Finally, we detected the phosphorylation of AMPK, ERK1/2, and HDAC4 in the heart from wild type and CKIP-1 transgenic mice after HU. The results revealed the reduced expression of CKIP-1 in the heart both from mice and monkey after simulated microgravity. Myocardial CKIP-1 overexpression protected from simulated microgravity-induced decline of cardiac function and loss of left ventricular mass. Histological analysis demonstrated CKIP-1 TG inhibited the decreases in the size of individual cardiomyocytes of mice after hindlimb unloading. CKIP-1 TG can inhibit the activation of HDAC4 and ERK1/2 and the inactivation of AMPK in heart of mice induced by simulated microgravity. These results demonstrated CKIP-1 was a suppressor of cardiac remodeling induced by simulated microgravity.
Highlights
Human cardiovascular system has adapted to Earth’s gravity of 1G, and cardiac muscle is well regulated in response to changes in loading conditions (Tuday and Berkowitz, 2007; Hill and Olson, 2008)
The changes in phosphorylation levels of HDAC4, AMPK, and ERK1/2 which were proved to be involved in cardiac remodeling of mice after hind limb unloading were detected in hearts of rhesus monkey after 45 days of bed rest
The results showed that following 45 days of bed rest, pathological cardiac remodeling signals-HDAC4 and ERK1/2 were activated, and physiological cardiac remodeling signal-AMPK were inactivated in monkey hearts (Supplementary Figure 2)
Summary
Human cardiovascular system has adapted to Earth’s gravity of 1G, and cardiac muscle is well regulated in response to changes in loading conditions (Tuday and Berkowitz, 2007; Hill and Olson, 2008). There are many important factors which can regulate cardiac remodeling induced by external or intrinsic stimuli, including AMPK, ERK1/2, and HDAC4 (Ling et al, 2012; Ruppert et al, 2013; Myers et al, 2017). Our previous study demonstrated that pathological cardiac remodeling signals, such as HDAC4 and ERK1/2, were activated, and physiological cardiac remodeling signals, such as AMPK, were inactivated in heart of mice after hindlimb unloading, which might lead to cardiac remodeling and decline of heart function (Zhong G. et al, 2016). The prevention of cardiac remodeling induced by simulated microgravity via inhibiting the changes of these signals activity need to be elucidated
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