Diallyl sulfide protects against dilated cardiomyopathy via inhibition of oxidative stress and apoptosis in mice.

Publisher: D. A. Spandidos Country of Publication: Greece NLM ID: 101475259 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1791-3004 (Electronic) Linking ISSN: 17912997 NLM ISO Abbreviation: Mol Med Rep Subsets: MEDLINE

Original Publication: Athens, Greece : D. A. Spandidos

Allyl Compounds/*pharmacology ; Apoptosis/*drug effects ; Cardiomyopathy, Dilated/*prevention & control ; Cardiotonic Agents/*pharmacology ; Oxidative Stress/*drug effects ; Sulfides/*pharmacology; Allyl Compounds/therapeutic use ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Cardiomyopathy, Dilated/pathology ; Cardiotonic Agents/therapeutic use ; Cell Line ; Cytochrome P-450 CYP2E1/metabolism ; Disease Models, Animal ; Enalaprilat/pharmacology ; Enalaprilat/therapeutic use ; Female ; Male ; Mice, Transgenic ; Mitochondria/drug effects ; Rats ; Sulfides/therapeutic use ; Troponin T/metabolism

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, cTnT ^R141W 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.

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Keywords: cytochrome P450 family 2 subfamily E member 1; diallyl sulfide; dilated cardiomyopathy; inhibitor of CYP2E1; oxidative stress

0 (Allyl Compounds)
0 (Angiotensin-Converting Enzyme Inhibitors)
0 (Cardiotonic Agents)
0 (Sulfides)
0 (Troponin T)
60G7CF7CWZ (allyl sulfide)
EC 1.14.13.- (Cytochrome P-450 CYP2E1)
EC 1.14.13.- (cytochrome P-450 2E1, mouse)
GV0O7ES0R3 (Enalaprilat)

Date Created: 20211015 Date Completed: 20220201 Latest Revision: 20220201

20240829

PMC8532119

10.3892/mmr.2021.12492

34651661