Dataset Information

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 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.

SUBMITTER: Dong W

PROVIDER: S-EPMC6354314 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Dong Wei W Guan Fei-Fei FF Zhang Xu X Gao Shan S Liu Ning N Chen Wei W Zhang Lian-Feng LF Lu Dan D

Animal models and experimental medicine 20180301 1

<h4>Background</h4>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<sup>R</sup> <sup>141W</sup> dilated cardiomyopathy (DCM) transgenic mice. Therefore, we tested whether rescued expression of Dhcr24 could prevent the development of DCM and its possible mechanism.<h4>Methods</h4>Heart tissue specific transgenic overe ...[more]

PMID: 30891546

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Project description:Cytochrome P450 family 2 subfamily E member 1 (CYP2E1) is a member of the cytochrome P450 enzyme family and catalyzes the metabolism of various substrates. CYP2E1 is upregulated in multiple heart diseases and causes damage mainly via the production of reactive oxygen species (ROS). In mice, increased CYP2E1 expression induces cardiac myocyte apoptosis, and knockdown of endogenous CYP2E1 can attenuate the pathological development of dilated cardiomyopathy (DCM). Nevertheless, targeted inhibition of CYP2E1 via the administration of drugs for the treatment of DCM remains elusive. Therefore, the present study aimed to investigate whether diallyl sulfide (DAS), a competitive inhibitor of CYP2E1, can be used to inhibit the development of the pathological process of DCM and identify its possible mechanism. Here, cTnTR141W transgenic mice, which developed typical DCM phenotypes, were used. Following treatment with DAS for 6 weeks, echocardiography, histological analysis and molecular marker detection were conducted to investigate the DAS‑induced improvement on myocardial function and morphology. Biochemical analysis, western blotting and TUNEL assays were used to detected ROS production and myocyte apoptosis. It was found that DAS improved the typical DCM phenotypes, including chamber dilation, wall thinning, fibrosis, poor myofibril organization and decreased ventricular blood ejection, as determined using echocardiographic and histopathological analyses. Furthermore, the regulatory mechanisms, including inhibition both of the oxidative stress levels and the mitochondria‑dependent apoptosis pathways, were involved in the effects of DAS. In particular, DAS showed advantages in terms of improved chamber dilation and dysfunction in model mice, and the improvement occurred in the early stage of the treatment compared with enalaprilat, an angiotensin‑converting enzyme inhibitor that has been widely used in the clinical treatment of DCM and HF. The current results demonstrated that DAS could protect against DCM via inhibition of oxidative stress and apoptosis. These findings also suggest that inhibition of CYP2E1 may be a valuable therapeutic strategy to control the development of heart diseases, especially those associated with CYP2E1 upregulation. Moreover, the development of DAS analogues with lower cytotoxicity and metabolic rate for CYP2E1 may be beneficial.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

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