Abstract：
Stress cardiomyopathy (SCM) is associated with cardiovascular mortality rates similar to acute coronary syndrome. Myocardial injuries driven by inflammatory mechanisms may in part account for the dismal prognosis of SCM. Currently, no inflammation-targeted therapies are available to mitigate SCM-associated myocardial injuries. In this study, acute catecholamine surge-induced SCM was modeled by stimulating the ovariectomized (OVX) mice with isoproterenol (ISO). The effects of ginsenoside Rb1 (Rb1) on SCM-associated myocardial injuries were assessed in the OVX-ISO compound mice. RAW 264.7 macrophages stimulated with calf thymus DNA (ctDNA) or STING agonist DMXAA were adopted to further understand the anti-inflammatory mechanisms of Rb1. The results show that estrogen deprivation increases the susceptibility to ISO-induced myocardial injuries. Rb1 mitigates myocardial injuries and attenuates cardiomyocyte necrosis as well as myocardial inflammation in the OVX-ISO mice. Bioinformatics analysis suggests that cytosolic DNA-sensing pathway is closely linked with ISO-triggered inflammatory responses and cell death in the heart. In macrophages, Rb1 lowers ctDNA-stimulated production of TNF-α, IL-6, CCL2 and IFN-β. RNA-seq analyses uncover that Rb1 offsets DNA-stimulated upregulation in multiple inflammatory response pathways and cytosolic DNA-sensing pathway. Furthermore, Rb1 directly mitigates DMXAA-stimulated STING activation and inflammatory responses in macrophages. In conclusion, the work here demonstrates for the first time that Rb1 protects against SCM-associated myocardial injuries in part by counteracting acute ISO stress-triggered cardiomyocyte necrosis and myocardial inflammation. Moreover, by evidencing that Rb1 downregulates cytosolic DNA-sensing machineries in macrophages, our findings warrant further investigation of therapeutic implications of the anti-inflammatory Rb1 in the treatment of SCM.
摘要：
应激性心肌病（SCM）与心血管死亡率类似于急性冠状动脉综合征。由炎症机制驱动的心肌损伤可能部分解释了SCM的不良预后。目前,目前尚无炎症靶向疗法可用于减轻SCM相关心肌损伤.在这项研究中,通过用异丙肾上腺素(ISO)刺激卵巢切除(OVX)小鼠建立儿茶酚胺浪涌诱导的SCM模型.在OVX-ISO化合物小鼠中评估人参皂苷Rb1(Rb1)对SCM相关心肌损伤的作用。采用小牛胸腺DNA（ctDNA）或STING激动剂DMXAA刺激RAW264.7巨噬细胞，以进一步了解Rb1的抗炎机制。结果表明，雌激素剥夺增加了ISO诱导的心肌损伤的易感性。Rb1减轻OVX-ISO小鼠的心肌损伤并减轻心肌细胞坏死以及心肌炎症。生物信息学分析表明，胞质DNA传感途径与ISO触发的炎症反应和心脏细胞死亡密切相关。在巨噬细胞中，Rb1降低ctDNA刺激的TNF-α的产生，IL-6、CCL2和IFN-β。RNA-seq分析揭示Rb1在多种炎症反应途径和胞质DNA感应途径中抵消DNA刺激的上调。此外，Rb1直接减轻巨噬细胞中DMXAA刺激的STING激活和炎症反应。总之,这项研究首次证明,Rb1部分通过对抗急性ISO应激触发的心肌细胞坏死和心肌炎症,保护SCM相关心肌损伤.此外，通过证明Rb1下调巨噬细胞中的胞浆DNA感应机制，我们的发现值得进一步研究抗炎Rb1在SCM治疗中的治疗意义.
