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

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 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 .

A variant near DHCR24 associates with microstructural properties of white matter and peripheral lipid metabolism in adolescents

“…According to previous studies, the demand for cholesterol by the brain is highest during development, including the brain maturation during childhood and adolescence [65], when it is required for myelination, among others [66]. Further, Dhcr24 expression is down-regulated during aging in wild-type mice [67]. In keeping with the aforementioned, we observed that the same variant is not associated with any of the studied phenotypes in SYS parents (N=527; data available on request).…”

Identification of Core Gene Biomarkers in Patients With Hypertrophic Cardiomyopathy

“…Activation of the PI3K/Akt pathway had a protective effect on dilated cardiomyopathy, but no study con rmed the protective effect of the PI3K/Akt pathway in HCM [54]. Therefore, the effect of the PI3K/Akt pathway in HCM can become a novel research direction in the future.…”

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway

“…Resveratrol improves cardiac function in the ischemic heart diseases and DCM through activating Akt-dependent pathway [41]. Dhcr24 protect against DCM also through upregulation of activated Akt [42]. We then investigated whether Cypher-deficiency induced cardiac apoptosis was associated with changes in the Akt survival pathway.…”