FFA-FABP4-FABP3介导的脂毒性参与阿霉素心血管损伤的分子细胞学机制

Despite the advent of targeted drugs, doxorubicin(DOX) remains a core component in the treatment of leukemia, breast cancer and other tumors. However, cardiotoxicity is a major limiting factor for the extensive application. At present, oxidative stress appears to be the common underlying cellular mechanism. This ROS hypothesis, however, has been tempered recently. Although the prominent expression of FABP4 as a critical mediator of the metabolic transporter is identified in adipocytes, the exact expression and function in cardiac tissue is still unknown. We found elevated expression of FABP4 in endothelial cell of the cardiac tissue, also the total protein contents of FABP4 in cardiac tissue were increased accompanied by elevated systemic TG and FFA. Also accumulated lipid droplets around mitochondria in cardiac cell were found in animals treated with DOX in our experiment. Therefore, the myocardial injury may be due to elevated FFA and TG in endothelial cells and cardiomyocytes which may be mediated by the FABP4/FABP3 as a transporter, then leads to cell apoptosis by stress response. Therefore, in this study, we will use the model of animal model and in vitro cardiomyocytes and vascular endothelial cells to analyze the role of Lipotoxicity in DOX-induced myocardial injury and its underlying molecular mechanism. This study can provide a new therapeutic target and strategy for early prevention and treatment of DOX-induced myocardial injury.

尽管靶向药物的应用，蒽环类药物仍然是白血病、乳腺癌等的核心用药。然而，心血管毒性是其大量应用的主要障碍。“氧化应激”损伤学说不能解释阿霉素所知心肌损伤的所有特征。FABP4作为细胞内脂质转运的关键介质，在脂肪细胞的表达已为人们所熟知，但在心脏组织的表达和作用尚知之甚少。我们在完成上一个课题时发现，动物给予阿霉素后，心肌内皮细胞有大量FABP4的表达，且心肌组织FABP4的总蛋白量增加，血液中TG和FFA升高，伴心肌细胞线粒体旁脂滴及脂褐素形成。鉴于阿霉素给药后动物均体形消瘦，结合FABP4存在于心脏内皮细胞，而FABP3主要存在于心肌细胞的发现，我们推测，FABP4可能介导FFA在内皮的转运，而FABP3可能介导FFA在心肌细胞的转运，进而参与了阿霉素升高血中FFA致心肌损伤的毒性作用。研究FABP4/FABP3在阿霉素脂毒性心肌病中的作用可为及早预防和治疗阿霉素性心肌损伤提供新的靶标。

阿霉素是临床常用的抗恶性肿瘤药物，具有抗瘤谱广及疗效好的特点，广泛用于血液系统肿瘤及恶性实体瘤的治疗。然而，剂量依赖性心脏毒性制约了其在临床的广泛应用。然而，阿霉素所致心脏毒性机制未明。深入研究阿霉素所致心肌损伤的分子机制，确定干预靶点并制定有效的干预策略显得至关重要。以前的研究大多聚焦于阿霉素对心肌的直接作用，我们的前期研究发现，阿霉素在引起心肌损伤前或同时伴有血液中游离脂肪酸的升高，但对其来源和其加重阿霉素所致心血管损伤的机制尚未做系统的研究。本项目从血液中游离脂肪酸的来源和去路角度确定了阿霉素所致心脏脂毒性心肌损伤的全新机制，并试图从多角度对这一心肌脂毒性进行干预。本项目的研究成果，阐明了阿霉素致心肌损伤的全新机制，也为临床防治阿霉素的心脏毒性提供了有效的干预策略和治疗靶点。