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

doi:10.1002/ame2.12007

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

Animal Model Exp Med. 2018 Apr 19;1(1):40-52. doi: 10.1002/ame2.12007. eCollection 2018 Mar.

Authors

Wei Dong¹, Fei-Fei Guan¹, Xu Zhang¹, Shan Gao¹, Ning Liu¹, Wei Chen¹, Lian-Feng Zhang¹, Dan Lu¹

Affiliation

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.

Abstract

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 cTnT^R ^141W 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^R ^141W 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^R ^141W and LMNA^E ^82K DCM mice. The transgenic overexpression of Dhcr24 significantly improves DCM phenotypes in cTnT^R ^141W 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.

Keywords: Dhcr24; apoptosis; dilated cardiomyopathy; gene expression and regulation.