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CLC number: R331.3

On-line Access: 2020-09-07

Received: 2020-01-21

Revision Accepted: 2020-05-11

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Journal of Zhejiang University SCIENCE B 2020 Vol.21 No.9 P.703-715


RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation

Author(s):  Xiao-He Zheng, lin-Lin Wang, Ming-Zhi Zheng, Jin-Jie Zhong, Ying-Ying Chen, Yue-Liang Shen

Affiliation(s):  Department of Basic Medicine Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China; more

Corresponding email(s):   bchenyy@zju.edu.cn, shenyueliang@zju.edu.cn

Key Words:  Hypothermic preservation, RGFP966, Yes-associated protein (YAP), Oxidative stress, Apoptosis

Xiao-He Zheng, lin-Lin Wang, Ming-Zhi Zheng, Jin-Jie Zhong, Ying-Ying Chen, Yue-Liang Shen. RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation[J]. Journal of Zhejiang University Science B, 2020, 21(9): 703-715.

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author="Xiao-He Zheng, lin-Lin Wang, Ming-Zhi Zheng, Jin-Jie Zhong, Ying-Ying Chen, Yue-Liang Shen",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation
%A Xiao-He Zheng
%A lin-Lin Wang
%A Ming-Zhi Zheng
%A Jin-Jie Zhong
%A Ying-Ying Chen
%A Yue-Liang Shen
%J Journal of Zhejiang University SCIENCE B
%V 21
%N 9
%P 703-715
%@ 1673-1581
%D 2020
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2000026

T1 - RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation
A1 - Xiao-He Zheng
A1 - lin-Lin Wang
A1 - Ming-Zhi Zheng
A1 - Jin-Jie Zhong
A1 - Ying-Ying Chen
A1 - Yue-Liang Shen
J0 - Journal of Zhejiang University Science B
VL - 21
IS - 9
SP - 703
EP - 715
%@ 1673-1581
Y1 - 2020
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2000026

oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4–6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP–transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.


方法:将大鼠离体心脏置于含有或不含有RGFP966的Celsior保存液中低温保存12 h后,于Langendorff灌流系统中复灌60 min,测定复灌期各项心功能指标.用Western blotting法分析Mst1和YAP蛋白表达和磷酸化水平.用TUNEL法测定心肌细胞凋亡情况.


Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


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