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

Abstract

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.

Quercetin inhibits the expression of MYC and CYP2E1 and reduces oxidative stress in the myocardium of spontaneously hypertensive rats

“…Such an increase in CYP2E1 expression has previously been demonstrated in hypertension and acute myocardial injury, and a key factor might be the upregulation of MYC (Guan et al, 2019). Clearly, increased expression of CYP2E1, a potent prooxidant factor, may be one of the most important reasons for the development of oxidative stress (Pang et al, 2021) in the myocardium, for which we found evidence in our experiment. It has been shown previously that altered expression of CYP2E1 may be a marker of various pathophysiological factors and conditions in the myocardium.…”

“…Therefore, an increase in CY-P2E1 expression in the early stages of heart failure development may be an adaptation of the myocardium to the conditions of altered energy exchange pathways, ensuring the preservation of the contractile function of the heart. On the other hand, oxidative stress, which may be caused by increased CYP2E1 expression, is one of the crucial pathological mechanisms in the development of heart disease (Guan et al, 2019;Pang et al, 2021).…”

“…We also noted some normalization of the balance between pro-and antioxidants in the heart, i.e., a decrease in the level of LPO and an increase in the activity of antioxidant enzymes. A decrease in the expression of CYP2E1 (as a potent prooxidant factor) could lead to a decrease in LPO levels (Pang et al, 2021). Moreover, the quercetin molecule can directly inhibit the activity of CYP2E1 by blocking the active site of the enzyme (Östlund et al, 2017).…”

Integrin β1/FAK/SRC signal pathway is involved in autism spectrum disorder inTspan7knockout rats

“…For protein assay, the brain tissues were, respectively, homogenized in lysis buffer containing RIPA buffer (50 mM Tris; 150 mM NaCl; 1% Triton X-100; 1% sodium deoxycholate; 0.1% SDS, P0013B; Beyotime), a protease inhibitor mixture (87785; Thermo Fisher Scientific), a phosphatase inhibitor cocktail (78420; Thermo Fisher Scientific), and 1 mM phenylmethyl-sulfonylfluoride (PMSF; 36978; Thermo Fisher Scientific) as previously reported ( Pang et al, 2021 ). The proteins in the cell membrane fraction and cytoplasm fraction were extracted using a ProteoExtract Subcellular Proteome Extraction Kit (539790; CALBIOCHEM).…”

Discovery of an evodiamine derivative for PI3K/AKT/GSK3β pathway activation and AD pathology improvement in mouse models

“…Western blotting was performed as previously described (Pang et al, 2021 ). The brain tissue homogenates were separated by SDS–PAGE and electroeluted onto nitrocellulose membranes (Immobilon NC; Millipore).…”