State Key Laboratory of Quality Research in Chinese Medicine (University of Macau), Avenue Padre Tomás Pereira S.J., Macao SAR, China; Institute of Chinese Medical Sciences, University of Macau, Avenue Padre Tomás Pereira S.J., Taipa, Macao SAR, China.
Int J Cardiol. 2013 Sep 30;168(2):1349-59. doi: 10.1016/j.ijcard.2012.12.012. Epub 2013 Jan 4.
Danshensu (3-(3,4-dihydroxyphenyl) lactic acid, DSS) is one of the most promising cardioprotective components in the root of Salvia miltiorrhiza but its poor chemical stability poses hurdles in its therapeutic development. It is therefore desirable to enhance the stability of DSS by chemical modification to improve its activities. In the present study, a novel DSS derivative named ADTM was synthesized and characterized for its cardioprotective properties.
Oxidative stress was induced in H9c2 cardiomyoblast cells by tert-butylhydroperoxide (t-BHP) and the protective effects of ADTM were evaluated. For in vivo study, adult rats were treated with vehicle, DSS, ADTM or amlodipine (n=6-8/group) for 24h before the induction of acute myocardial ischemia. At the end of each experiment, infarct size was measured. Underlying the mechanisms of the cardioprotective effects of ADTM were further investigated in H9c2 cells and rat myocardium by evaluating the effects of Nrf2 (NF-E2-related factor 2) and Akt/PI3K pathways.
ADTM was approximately 10 times more effective than DSS against t-BHP-induced cell injury in H9c2 cells. In rat myocardial ischemia model, ADTM treatment significantly alleviated myocardial infarction. Akt/PI3K and Nrf2 pathways were demonstrated to be involved in both in vitro and in vivo experiments.
These results demonstrated that ADTM displayed much better cardioprotective effects than its parent compounds both in vitro and in vivo. This cardioprotection is mediated, at least in part, through Akt/PI3K and Nrf2 pathways. This novel compound represents a promising candidate for the treatment of cardiovascular diseases (CVDs), particularly myocardial infarction.
丹参素（3-（3,4-二羟基苯基）乳酸，DSS）是丹参根中最有前途的心脏保护成分之一，但它的化学稳定性差，这对其治疗开发构成了障碍。因此，通过化学修饰来提高 DSS 的稳定性，以提高其活性是可取的。在本研究中，合成了一种新型的 DSS 衍生物，命名为 ADTM，并对其心脏保护特性进行了表征。
用叔丁基过氧化氢（t-BHP）诱导 H9c2 心肌细胞产生氧化应激，评价 ADTM 的保护作用。在体内研究中，成年大鼠用载体、DSS、ADTM 或氨氯地平（每组 n=6-8）预处理 24 小时，然后诱导急性心肌缺血。在每个实验结束时，测量梗死面积。通过评估 Nrf2（NF-E2 相关因子 2）和 Akt/PI3K 途径，进一步研究 ADTM 对 H9c2 细胞和大鼠心肌的心脏保护作用的机制。
ADTM 对 H9c2 细胞中 t-BHP 诱导的细胞损伤的作用比 DSS 强约 10 倍。在大鼠心肌缺血模型中，ADTM 治疗显著减轻心肌梗死。Akt/PI3K 和 Nrf2 途径在体外和体内实验中均被证明参与其中。
这些结果表明，ADTM 在体外和体内均显示出比其母体化合物更好的心脏保护作用。这种心脏保护作用至少部分是通过 Akt/PI3K 和 Nrf2 途径介导的。这种新型化合物代表了治疗心血管疾病（CVDs），特别是心肌梗死的有前途的候选药物。
