Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice

Wei Dong; Fei-fei Guan; Xu Zhang; Shan Gao; Ning Liu; Wei Chen; Lian-feng Zhang; Dan Lu

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Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice

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Background:24-dehydrocholesterol reductase(Dhcr24)catalyzes the last step of cholesterol biosynthesis,which is required for normal development and antiapoptotic activities of tissues.We found that Dhcr24 expression decreased in the cTnTR141W dilated cardiomyopathy(DCM)transgenic mice.Therefore,we tested whether rescued expression of Dhcr24 could prevent the development of DCM and its possible mechanism.Methods:Heart tissue specific transgenic overexpression mice of Dhcr24 was generated,then was crossed to cTnT^R141W mouse to obtain the double transgenic mouse(DTG).The phenotypes were demonstrated by the survival,cardiac geometry and function analysis,as well as microstructural and ultrastructural observations based on echocardiography and histology examination.The pathway and apoptosis were analysed by western blotting and TUNEL assay in vivo and in vitro.Results:We find that Dhcr24 decreased in hearts tissues of cTnT^R141W and LMNA^E82K DCM mice.The transgenic overexpression of Dhcr24 significantly improves DCM phenotypes in cTnT^R141W mice,and activates PI3K/Akt/HKII pathway,followed by a reduction of the translocation of Bax and release of cytochrome c,caspase-9 and caspase-3 activation and myocyte apoptosis.Knockdown the expression of Dhcr24 reduces the activation of PI3K/Akt/HKII pathway and inhibition of the mitochondrial-dependent apoptosis.The anti-apoptotic effect of Dhcr24 could be completely removed by the inhibition of PI3K pathway and partly removed by the HKII inhibitor in H9c2 cell line.Conclusion:Compensatory expression of Dhcr24 protect against DCM through activated PI3K/Akt/HKII pathway and reduce Bax translocation.This is the first investigation for the molecular mechanism of Dhcr24 participate in development of DCM.

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来源
《动物模型与实验医学（英文）》 |2018年第1期|P.40-52|共13页
作者
Wei Dong; Fei-fei Guan; Xu Zhang; Shan Gao; Ning Liu; Wei Chen; Lian-feng Zhang; Dan Lu;
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作者单位

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

[1]Key Laboratory of Human Disease Comparative Medicine;

NHFPC;

Institute of Laboratory Animal Science;

Chinese Academy of Medical Sciences&Comparative Medical Center;

Peking Union Medical College;

Beijing;

China;

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原文格式 PDF
正文语种 CHI
中图分类医药、卫生;
关键词
apoptosis; Dhcr24; dilated cardiomyopathy; gene expression and regulation;

机译：细胞凋亡;Dhcr24;扩张型心肌病;基因表达与调控;

Dhcr24 activates the PI3K/Akt/HKII pathway and protects against dilated cardiomyopathy in mice

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