栀子配伍丹参调控Grsf1/GPx4和Nrf2依赖性铁死亡保护氧化应激微环境下心肌的机制研究

Oxidative stress microenvironment is one of the key factors for myocardial cell injury and hypertrophy. Recent studies have found that ferroptosis associated with oxidative stress regulated by GPx4 and Nrf2 is an important means of death for cardiomyocytes. Iron overload can induce ferroptosis. The research group proposed that the medical treatment of iron overload can be understood from the Yudu and the treatment of Jiedu Huoxue. Previous studies have found that gardenoside and danphenolic acid B can activate Nrf2/ARE signaling pathway and have clear anti-oxidative effect. Based on this, this study proceed the scientific hypothesis of that the drug may protect myocardium in oxidative stress microenvironment by inhibiting ferroptosis via enzymatic GPx4 and transcription factor Nrf2, which may activate the regulation of ferroptosis. In this study, myocardial cell ferroptosis was used as a research target. From the perspective of iron complexation, iron homeostasis regulation, cystine transport pathway and Nrf2 signal regulation, the mechanism of controlling the ferroptosis of myocardial cells was studied. This study provides a new way to clarify the potential effect and mechanism of TCM on myocardium in oxidative stress microenvironment, and provides a scientific basis for the clinical application of Jiedu Huoxue method in the field of myocardial protection.

氧化应激微环境是心肌细胞损伤与肥大的关键因素之一。新近研究发现受GPx4和Nrf2调控的、与氧化应激相关的“Ferroptosis（铁死亡）”是心肌细胞的重要死亡方式，细胞内铁离子转运异常相关的铁过载可诱发铁死亡。课题组提出铁过载中医学可从“瘀毒”的角度认识和解毒活血的治法，前期研究发现其代表药对“栀子-丹参”有效活性成分栀子苷和丹酚酸B可激活Nrf2/ARE信号通路而具有明确的抗氧化作用。基于此，本研究提出该药对可能激活调节铁死亡的酶类GPx4和转录因子Nrf2而抑制铁死亡，保护氧化应激微环境下心肌的科学假说。本研究以心肌细胞铁死亡为研究靶点，从铁络合、铁稳态的调节、胱氨酸转运通路以及Nrf2信号调控的角度，研究“栀子-丹参”药对调控上述环节防治心肌细胞铁死亡的机制。本研究为阐明中药保护氧化应激微环境下心肌的潜在效应和机制提供了新思路，对临床解毒活血法在心肌保护领域的应用提供科学依据。

缺血性心脏病在世界范围内具有较高的发病率和致死率，但是心肌组织在缺血缺氧过程中的发病机理尚不完全清楚。研究显示，在心肌梗死发生时，心肌细胞发生铁死亡，因此，阻断心肌细胞铁死亡可能成为治疗缺血性心脏病的潜在靶点。丹参-栀子是传统医学中治疗心脏疾病的经典组合，在多项基础和临床研究中证实其具有心梗后心肌保护的作用。然而其对阻断心肌细胞铁死亡尚缺乏相关研究，基于此，我们拟结合体内体外研究，利用形态学、分子生物学等研究方法，观察丹参、栀子药对及其重要活性成分对心肌铁死亡保护作用，并解析其发挥作用的重要靶点。结果显示，丹参-栀子药对及其活性成分丹酚酸B，栀子苷可减轻心肌细胞铁死亡发生水平，并进一步探究发现其可通过上调grsf1/gpx4 及nrf2 通路增强心肌抗氧化水平，从而达到抑制铁死亡的作用。

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