Department of Pediatrics, China Medical University Beigang Hospital, Yunlin, Taiwan, ROC; Department of Biological Science & Technology College of Life Sciences, China Medical University, Taichung, Taiwan, ROC.
Int J Cardiol. 2013 Sep 30;168(2):1286-97. doi: 10.1016/j.ijcard.2012.12.004. Epub 2013 Feb 27.
Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG).
Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 μM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucose-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW.
Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2-regulated antioxidant enzymes in cardiomyocytes exposed to HG.
高血糖诱导的活性氧（ROS）生成导致糖尿病心肌病的发展。核因子 E2 相关因子 2（Nrf2）是一种氧化还原感应转录因子，可诱导抗氧化酶的表达。二烯丙基三硫化物（DATS）是大蒜油中含硫化合物中最强的抗氧化剂。我们研究了 DATS 是否通过 Nrf2 介导的抗氧化酶激活抑制高糖（HG）暴露的心肌细胞中 ROS 的产生。
用 HG 处理 H9c2 细胞会导致细胞内 ROS 水平和半胱天冬酶-3 活性增加，而 DATS（10 μM）的给药则明显降低了这两种物质的水平。DATS 处理可显著增加 Nrf2 蛋白的稳定性和核转位，上调下游基因 HO-1，并抑制其抑制因子 Keap1。然而，在用 Nrf2 特异性 siRNA 转染的细胞中，DATS 并未抑制细胞凋亡。LY294002（PI3K 抑制剂）或 PI3K 特异性 siRNA 抑制 PI3K/Akt 信号通路不仅降低了 DATS 诱导的 Nrf2 介导的 HO-1 表达水平，而且还减弱了 DATS 的保护作用。在高糖暴露的新生原代心肌细胞和用 DATS（40 mg/kg BW）处理的链脲佐菌素诱导的糖尿病大鼠中也观察到了类似的结果。
我们的研究结果表明，DATS 通过上调 PI3K/Akt/Nrf2 通路来保护心肌细胞免受高血糖诱导的 ROS 介导的凋亡，该通路进一步激活了高糖暴露的心肌细胞中 Nrf2 调节的抗氧化酶。
