Inhibition of OAT1/3 and CMPF uptake attenuates myocardial ischemia-induced chronic heart failure via decreasing fatty acid oxidation and the therapeutic effects of ruscogenin.
Inhibition of OAT1/3 and CMPF uptake attenuates myocardial ischemia-induced chronic heart failure via decreasing fatty acid oxidation and the therapeutic effects of ruscogenin.
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DOI：
10.1016/j.trsl.2023.06.001
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发表时间：
2023-06
期刊：
影响因子：
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通讯作者：
Qiong Lai;Xiaozhou Zhu;Lu Zhang;J. Kou;Fu-ming Liu;Boyang Yu;Fang Li
中科院分区：
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作者：
Qiong Lai;Xiaozhou Zhu;Lu Zhang;J. Kou;Fu-ming Liu;Boyang Yu;Fang Li
慢性心力衰竭（CHF）是一种慢性疾病，在世界范围内的老年人中非常普遍。早期诊断和治疗对于预防CHF的发展至关重要。在此，我们的目的是确定新的诊断生物标志物，治疗靶点和药物CHF。非靶向代谢组学分析已被用于表征CHF患者和健康人之间的不同代谢组学谱。同时，靶向代谢组学研究表明，CHF患者和冠状动脉结扎诱导的CHF小鼠血清中3-羧基-4-甲基-5-丙基-2-呋喃丙酸（CMPF）升高。随后，我们首次观察到CMPF升高通过增强脂肪酸氧化（FAO）而损害心功能，加重心肌损伤。有趣的是，已发现抑制责任转运蛋白有机阴离子转运蛋白1/3（OAT 1/3）可降低冠状动脉结扎诱导的CHF小鼠的CMPF水平，并抑制FAO相关关键蛋白的表达，包括过氧化物酶体增殖物激活受体α、过氧化物酶体增殖激活受体-α、肉毒碱棕榈酰转移酶1和丙二酰CoA脱羧酶。同时，OAT 1/3抑制剂在心功能和组织学损伤方面表现出良好的改善作用。基于上述发现，采用分子对接的方法筛选出了靶向OAT 1/3的潜在治疗药物，发现鲁斯可皂苷元（罗斯）与OAT 1和OAT 3具有很强的结合能力。接下来，证实了罗斯可显著降低CHF小鼠心脏组织中OAT 1/3和CMPF水平的表达，以及抑制FAO相关蛋白的表达。罗斯能有效改善心功能、心肌纤维化及形态学损害。总之，本研究提供了一个潜在的代谢标志物CMPF和CHF的新靶点OAT 1/3，它们被证明参与FAO。罗斯通过调节OAT 1/3而被确定为CHF的潜在抗FAO药物。
Chronic heart failure (CHF) as a long-term disease is highly prevalent in elder people worldwide. Early diagnosis and treatments are crucial for preventing the development of CHF. Herein, we aimed to identify novel diagnostic biomarker, therapeutic target and drug for CHF. Untargeted metabolomic analysis has been used to characterize the different metabolomic profile between CHF patients and healthy people. Meanwhile, the targeted metabolomic study demonstrated the elevation of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) in the serum of CHF patients and coronary artery ligation-induced CHF mice. Subsequently, we firstly observed that elevation of CMPF impaired cardiac function and aggravated myocardial injury by enhancing fatty acid oxidation (FAO). Interestingly, inhibition of responsible transporters organic anion transporter 1/3 (OAT1/3) has been found to decrease the CMPF level, and suppress FAO-related key protein expressions including peroxisome proliferator-activated receptor alpha, peroxisome proliferative activated receptor-α, carnitine palmitoyl transferase 1, and malonyl CoA decarboxylase in coronary artery ligation-induced CHF mice. Meanwhile, the inhibitor of OAT1/3 presented an excellent improvement in cardiac function and histological injury. Based on the above findings, molecular docking was adopted to screen the potential therapeutic drug targeting OAT1/3, and ruscogenin (RUS) exhibited a great binding affinity with OAT1 and OAT3. Next, it was verified that RUS could remarkedly decrease the expression of OAT1/3 and CMPF levels in heart tissue of CHF mice, as well as suppress the expression of FAO-related proteins. What's more, RUS can effectively improve cardiac function, myocardial fibrosis and morphological damage. Collectively, this study provided a potential metabolic marker CMPF and novel target OAT1/3 for CHF, which were demonstrated to be involved in FAO. And RUS was identified as a potential anti-FAO drug for CHF by regulating OAT1/3.