参麦注射液调节阿霉素诱导的心肌线粒体功能紊乱保护心脏的作用机制研究

Doxorubicin(DOX) is a highly effective antibiotic used to treat several types of tumor. However, the clinical use of DOX is limited by the occurrence of a dose-related cardiac toxicity. DOX-induced cardiotoxicity is a loss of calcium-loading capacity by mitochondria and induction of the mitochondrial permeability transition pore (mPTP). The activation of the survival signaling PI3K-Akt pathway is linked to the inhibition of mPTP opening. Decreased response of Akt activation, the mPTP opening might be increased linking aging to functional and structural derangements of mitochondria. Qi deficiency is the basic pathogenesis in DOX-induced cardiotoxicity and senescence in Traditional Chinese Medicine. Yiqi Yangyin Shengjin Chinese herb preparation ShenMai injection have been applied to protects cardiac function against cardiotoxicity induced by doxorubicin. Our preliminary studies found ShenMai injection can improve the mitochondrial calcium retention capacity, and inhibite the mPTP opening. The objective of the research are to clarify the mechanisms that ShenMai injection exert cardioprotective effects against DOX-induced cardiotoxicity in young and ageing animals based mitochondrial pathways. We expect to clarify the basic theory of “Qi and Jin deficiency” and “tonifying qi and jin” in traditional Chinese medical science at mitochondrial level. This project help us research cardioprotective Chinese medicine better and promote the development of Chinese Medicine Theory.

阿霉素抗肿瘤疗效确切，但严重的心脏毒性使其临床应用受到较大限制。阿霉素造成的心脏损伤是以“线粒体钙载能力降低导致的通透性转换孔(mPTP)开放”为主的线粒体功能紊乱；PI3K-Akt生存信号通路激活是抑制mPTP开放的重要通路，Akt激活能力降低，心脏mPTP开放等线粒体功能障碍也是衰老的重要特征，两种疾病同以“气虚津亏”虚证为基本病机。益气养阴生津中药参麦注射液具有心肌保护作用，临床常作为肿瘤患者化疗后的辅助用药，用以减轻阿霉素的心脏毒性。前期研究发现，参麦注射液能提高线粒体钙载能力，抑制mPTP开放。故本研究以“决定线粒体生死存亡的mPTP”为关键点，从激活Akt通路，调节线粒体呼吸、氧化应激、钙代谢等线粒体途径，阐述参麦注射液拮抗阿霉素对正常及衰老机体心脏损伤的作用机制，从线粒体角度阐释“气虚津亏”的科学内涵及“益气生津”药物的作用机制，有助于心肌保护中药的研究及中医理论水平的提高。

阿霉素(DOX)抗肿瘤疗效确切，但严重的心脏毒性使其临床应用受到较大限制。DOX造成的心脏损伤是以线粒体功能紊乱为主；PI3K-Akt生存信号通路激活是抑制mPTP开放保护线粒体功能的重要通路，Akt激活能力降低，线粒体功能障碍也是衰老的重要特征，两种疾病同以“气虚津亏”虚证为基本病机。益气养阴生津中药参麦注射液(SMI)具有心肌保护作用，临床常作为肿瘤患者化疗后的辅助用药，用以减轻DOX的心脏毒性。前期研究已经证实SMI能提高线粒体钙载能力，抑制mPTP开放。本课题研究SMI激活Akt通路，调节线粒体呼吸、氧化应激等线粒体途径，阐述SMI/人参总皂苷拮抗DOX对正常及衰老机体心脏损伤的作用机制。实施过程中应用DOX诱导的心肌损伤动物和细胞模型，证明了SMI通过激活AMPK和PI3K/Akt/GSK-3β信号通路来维持线粒体稳态，从而减轻DOX诱导的心肌损伤，改善心脏功能；建立D-半乳糖诱导急性衰老小鼠模型，发现老龄小鼠存在心肌线粒体功能下降，SMI主要有效成分人参总皂苷通过降低线粒体呼吸链复合物活性，增加心脏线粒体质子漏，改善粒体呼吸O2通量、脂肪酸β氧化以及NADH型底物连接状态下线粒体磷酸化作用，降低线粒体H2O2通量、减轻氧化应激；提高线粒体ΔΨ、RCR和氧化磷酸化耦合率，促使线粒体ATP合成增加，改善小鼠衰老；线粒体功能的改善可能与降低血糖、减轻晚期糖基化终产物积累及炎症反应有关。此外还从线粒体角度进行了参麦注射液抗心肌细胞缺氧复氧损伤的研究。课题为SMI临床作为肿瘤患者DOX化疗后的辅助用药提供实验依据,从线粒体角度阐释“气虚津亏”的科学内涵及“益气生津”药物的作用机制，有助于心肌保护中药的研究及中医理论水平的提高。