DOI: 10.1002/ame2.12007
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
摘要：Background: 24-dehydrocholesterol reductase (Dhcr24) catalyzes the last step of cholesterol biosynthesis, which is required for normal development and anti-apoptotic 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 gen-erated, then was crossed to cTnTR141W 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 cTnTR141W and LMNAE82K DCM mice. The transgenic overexpression of Dhcr24 significantly improves DCM phenotypes in cTnTR141W mice, and activates PI3K/Akt/HKII path-way, 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 inhibi-tion 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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资助基金：The present work was supported by the National Science and Technology Support Project(2015BAI08B01)CAMS Innovation Fund for Medical Sciences(CAMS-I2M)CAMS Innovation Fund for Medical Sciences( 2016-I2M-1-015)Beijing Natural Science Foundation(5172027)
论文发表日期：2018-01-01
在线出版日期：2025-08-15（本平台首次上网日期，不代表文献的发表时间）
页数：13( 40-52 )
英文信息