Diallyl Trisulfide Suppresses High-Glucose-Induced Cardiomyocyte Apoptosis by Targeting Reactive Oxygen Species-Mediated Hypoxia-Inducible Factor-1α/Insulin-like Growth Factor Binding Protein 3 Activation

Abstract

It has been reported that 80% of diabetic patients die due to cardiovascular diseases. We previously demonstrated that activated hypoxia-inducible factor-1α (HIF-1 α)/insulin-like growth factor binding protein-3 (IGFBP-3) signaling by reactive oxygen species (ROS)-regulated prolyl hydroxylase domain-containing protein (PHD) is involved in high-glucose (HG)-induced cardiac apoptosis. Diallyl trisulfide (DATS), a garlic component, shows the strongest inhibitory effect on diabetic cardiomyopathy. In this study, we investigated whether HIF-1α/IGFBP-3 signaling governs the antiapoptotic effect by DATS on HG-exposed cardiomyocytes. It was observed that significantly increased levels of cell apoptosis and decreased Akt phosphorylation were reversed by DATS in HG-exposed cardiac cells. H2O2 and PHD small interfering RNA treatments increased HIF-1α and IGFBP-3 protein levels, which were decreased by DATS treatment. Overexpression of HIF-1α and IGFBP-3 increased HG-induced cell apoptosis, which was suppressed by DATS. The coimmunoprecipitation assay results showed that DATS not only increased the IGF-1 level and reduced IGFBP-3 level but also suppressed their extracellular association for cardiac cells exposed to HG. Experiments using neonatal cardiomyocytes and hearts showed similar results. These findings indicate that the effect of ROS-regulated PHD on the activation of HIF-1α/IGFBP-3 signaling governs the antiapoptotic effect by DATS on HG-exposed cardiomyocytes.

Thiosulfinate-Enriched Allium sativum Extract Exhibits Differential Effects between Healthy and Sepsis Patients: The Implication of HIF-1α

“…Some other studies have proposed regulation of this pathway by garlic-derived compounds and similar antioxidant phytochemicals [ 41 , 42 ]. Along these lines, allicin and diallyl trisulfide suppressed the HIF-1α pathway in cancer and other pathogenic contexts [ 3 , 4 , 7 , 13 , 30 ]. Thus, we propose the suppression of the HIF-1α pathway and the subsequent decrease in IRAK-M as the possible underlying cause of the differential/dual effects of TASE in monocytes.…”

“…Treatment with allicin has been shown to protect against the detrimental effects of nephropathy in a model of diabetes due to its antioxidant capacity and Nrf2 induction [ 6 ]. Moreover, this compound reduced reactive oxygen species (ROS) production in murine aortic endothelial cells that had undergone high glucose/hypoxia-induced injury [ 7 ].…”

Activation of PI3K/Akt mediates the protective effect of diallyl trisulfide on doxorubicin induced cardiac apoptosis

“…Diallyl trisulfide (DATS), an important oil-soluble organosulfur component and the most potent antioxidant in garlic oil, has been reported to inhibit the proliferation of various human cancer cells, including those originating from colon, lung, skin, and breast cancers ( Zhang et al, 2020 ). Modern pharmacological studies have claimed that DATS has antiinflammation and antioxidant properties ( Tsai et al, 2013 , Kuo et al, 2013 , Lin et al, 2021 ). A study of diabetic rats treated with garlic oil revealed that the activated PI3K/Akt/Nrf2-Keap1 signaling could alleviate cardiac oxidative stress ( Padiya et al, 2014 , Ou et al, 2010 ).…”