STAT3调控胱硫醚-γ-裂解酶在硫化氢及其内源性供体治疗蒽环类药物心肌损伤中的作用及机制研究

Doxorubicin (Dox), an anthracycline derivative, is effective for a broad range of human malignancies. However, its clinical use is challenged by the risk of serious cardiotoxicity, which causes dilated cardiac dysfunction and congestive heart failure associated with the development of irreversible cardiomyopathy. In the process of cardiac failure, STAT3-mediated signaling transduction is closely related with the survival and apoptosis of cardiomyocytes, inflammatory responses, angiogenesis, oxidative stress, and regulation of DNA and mitochondrial function. Our previous research has revealed that hydrogen sulfide (H2S), and its endogenous donor—S-propargyl-cysteine (SPRC), exerts profound therapeutic effects on Dox cardiotoxicity via gp130/STAT3 signaling activation. Additionally, the cardioprotective effect of SPRC is based on enhanced activity of cystathionine-γ-lyase (CSE) and subsequently augmented H2S level in mammalian plasma and hearts. However, the protective role and mechanism of STAT3-CSE interaction in H2S/SPRC against cardiac injury is not well-established. Therefore, the current project is performed to：(1) verify STAT3 regulation of CSE is involved in the therapeutic effect of anti-anthracycline cardiomyopathy by H2S/SPRC; (2) elucidate H2S/SPRC inhibits cardiomyocyte apoptosis, antagonizes DNA damage and mitochondrial dysfunction, and alleviates heart failure through STAT3-CSE signal modulation, utilizing cardiomyocyte-restricted STAT3 KO mice and CSE KO mice. This study will offer a novel molecular basis and therapeutic strategy for the treatment of heart failure by H2S/SPRC

以多柔比星为代表的蒽环类药物在抗肿瘤临床应用中有严重的心肌毒性，可引起扩张性心功能障碍及充血性心力衰竭伴随不可逆性心肌病。心衰过程中，STAT3信号转导与心肌细胞存活与凋亡、炎症反应、血管生成、氧化应激、DNA及线粒体功能调节密切相关。我们前期研究成果表明H2S及其内源性供体SPRC可以调控gp130/STAT3信号拮抗Dox心肌毒性；且SPRC通过激活CSE产生H2S发挥心脏保护功能。目前尚未有STAT3与CSE的相互作用参与H2S心肌保护的报道。因此，本研究课题拟：①揭示STAT3调控CSE参与H2S/SPRC改善Dox心肌损伤过程；②利用心肌特异性STAT3敲除小鼠和CSE敲除小鼠，阐明H2S/SPRC通过调节STAT3-CSE信号发挥治疗Dox诱导的心肌细胞凋亡、DNA和线粒体损伤及心力衰竭的保护作用。本研究将为H2S/SPRC治疗蒽环类药物所致的心力衰竭提供新的分子基础和治疗策略

鉴于越来越多的肿瘤患者伴有Dox引起的心肌毒性，开发针对其这一不良反应的治疗药物成为刻不容缓的举措。研究表明心肌特异性过表达STAT3小鼠较野生型小鼠不易患Dox心肌病，提示适度上调STAT3活性可以成为防治Dox心肌毒性的有效策略。我们前期研究结果表明内源性H2S供体SPRC具有显著的心血管保护作用，表现在抗氧化、抗炎和促心脏血管新生等方面。然而关于SPRC拮抗Dox诱导心肌毒性反应的作用及机制尚无报道。在本课题中，我们通过体内外实验研究了SPRC治疗Dox心肌损伤的作用并深入探讨了调控STAT3信号通路可能是SPRC改善Dox心肌病的作用机制。在Dox诱导的原代心肌细胞中，SPRC通过激活STAT3提高CSE蛋白表达水平，增强STAT3与CSE相互作用，并调控STAT3下游蛋白表达。在Dox诱导的小鼠心肌中，SPRC可以通过激活STAT3改善心功能异常及心肌病理损伤，抑制心肌细胞坏死凋亡。因此，SPRC通过活化STAT3介导的CSE发挥治疗Dox诱导的心肌凋亡及心力衰竭的作用。本研究将为H2S/SPRC治疗蒽环类药物所致的心力衰竭提供新的分子基础和治疗策略。