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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  PI 3K/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  PI 3K/Akt/ HKII  pathway and inhibition of the mitochondrial‐dependent apoptosis. The anti‐apoptotic effect of Dhcr24 could be completely removed by the inhibition of  PI 3K pathway and partly removed by the  HKII  inhibitor in H9c2 cell line.    Conclusion  Compensatory expression of Dhcr24 protect against  DCM  through activated  PI 3K/Akt/ HKII  pathway and reduce Bax translocation. This is the first investigation for the molecular mechanism of Dhcr24 participate in development of  DCM .

Dhcr24 activates the PI 3K/Akt/ HKII pathway and protects against dilated cardiomyopathy in mice