School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China.
School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, China.
Biomed Pharmacother. 2023 Jul;163:114868. doi: 10.1016/j.biopha.2023.114868. Epub 2023 May 16.
Retinoid X receptor alpha (RXRα) is a nuclear transcription factor that extensively regulates energy metabolism in cardiovascular diseases. Identification of targeted RXRα drugs for heart failure (HF) therapy is urgently needed. Neocryptotanshinone (NCTS) is a component derived from Salvia miltiorrhiza Bunge, the effect and mechanism of which for treating HF have not been reported. The goal of this study was to explore the pharmacological effects of NCTS on energy metabolism to protect against HF post-acute myocardial infarction (AMI) via RXRα. We established a left anterior descending artery ligation-induced HF post-AMI model in mice and an oxygen-glucose deprivation-reperfusion-induced H9c2 cell model to investigate the cardioprotective effect of NCTS. Component-target binding techniques, surface plasmon resonance (SPR), microscale thermophoresis (MST) and small interfering RNA (siRNA) transfection were applied to explore the potential mechanism by which NCTS targets RXRα. The results showed that NCTS protects the heart against ischaemic damage, evidenced by improvement of cardiac dysfunction and attenuation of cellular hypoxic injury. Importantly, the SPR and MST results showed that NCTS has a high binding affinity for RXRα. Meanwhile, the critical downstream target genes of RXRα/PPARα, which are involved in fatty acid metabolism, including Cd36 and Cpt1a, were upregulated under NCTS treatment. Moreover, NCTS enhanced TFAM levels, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate levels by activating RXRα. In conclusion, we confirmed that NCTS improves myocardial energy metabolism, including fatty acid oxidation and mitochondrial biogenesis, by regulating the RXRα/PPARα pathway in mice with HF post-AMI.
视黄醇 X 受体α（RXRα）是一种核转录因子，广泛调节心血管疾病中的能量代谢。迫切需要鉴定针对心力衰竭（HF）治疗的靶向 RXRα 药物。新隐丹参酮（NCTS）是一种源自丹参的成分，其治疗 HF 的作用和机制尚未报道。本研究旨在通过 RXRα 探索 NCTS 对能量代谢的药理作用，以保护急性心肌梗死后 HF。我们在小鼠中建立了左前降支结扎诱导的 HF 后 AMI 模型和氧葡萄糖剥夺再灌注诱导的 H9c2 细胞模型，以研究 NCTS 的心脏保护作用。应用成分-靶标结合技术、表面等离子体共振（SPR）、微量热泳动（MST）和小干扰 RNA（siRNA）转染技术，探讨 NCTS 靶向 RXRα 的潜在机制。结果表明，NCTS 通过改善心脏功能和减轻细胞缺氧损伤来保护心脏免受缺血损伤。重要的是，SPR 和 MST 结果表明，NCTS 与 RXRα 具有高结合亲和力。同时，RXRα/PPARα下游的关键靶基因，参与脂肪酸代谢，包括 Cd36 和 Cpt1a，在 NCTS 处理下上调。此外，NCTS 通过激活 RXRα 增加 TFAM 水平、促进线粒体生物发生和增加心肌三磷酸腺苷水平，改善心肌能量代谢，包括脂肪酸氧化和线粒体生物发生。总之，我们证实 NCTS 通过调节 HF 后 AMI 小鼠的 RXRα/PPARα 通路改善心肌能量代谢，包括脂肪酸氧化和线粒体生物发生。
