The Mechanism Study Of Qihuang-Zhuyu Decoction Against Post-MI Depression-like Behavior Via Exo-LncRNA Lgr6 Mediated NLRP3 Inflammasome Signal Transduction

BACKGROUND:Post-myocardial infarction depression is a syndrome that occurs after myocardial infarction and manifests as a series of depressive symptoms and corresponding somatic symptoms.It is one of the common treatable complications of myocardial infarction,and if not detected and treated in time,it will affect the recovery of cardiac function and the ability of patients to return to society after myocardial infarction.In the past,we always superficially thought that post-myocardial infarction depression was caused by MI patients' excessive concern about their condition.With the academic debate on whether psychiatric disorders have an underlying material basis,it is gradually believed that post-myocardial infarction depression has molecular mechanisms involved in addition to myocardial infarction.At present,there is no accepted treatment plan for post-myocardial infarction depression.Professor Chen Xiaohu proposed that post-infarction depression should be treated by detoxifying the liver and relieving depression as the symptomatic treatment,and tonifying the heart qi and unblocking the heart chakra as the fundamental treatment,advocating the use of Astragalus membranaceus,Huangjing,Sumac,Safflower and Leech to treat post-myocardial infarction depression.OBJECTIVE:To reveal the mechanism of post-myocardial infarction depression,to explain the principle of Qihuang-Zhuyu Formula in treating post-myocardial infarction depression,and to deepen the understanding of post-myocardial infarction depression.METHODS:(1)A standard combination of Qihuang-Zhuyu Formula prepared and the components were identified.(2)To retrospectively study the peripheral IL-1? levels in patients with acute myocardial infarction and the effect of Qihuang-Zhuyu Formula on IL-1?.(2)To observe the effect of exosomes on HT-22 cells,NLRP3 Inflammasome signaling after cardiomyocyte hypoxia,and to screen effector molecules in exosomes and verify the function of effector molecules using C57BL/6 mammary mouse primary cardiomyocyte nuclei mouse hippocampal neuronal cells HT-22.As well as the effect of Qihuang-Zhuyu Formula containing serum on this process.(3)To validate the effects of Qihuang-Zhuyu Formula on neuroinflammation and behavior of the brain after myocardial infarction in mice by constructing a C57BL/6 mouse myocardial infarction model.(4)Animal experiments were conducted to verify the effects of exosomes and exosome-carried effector molecules.RESULTS:(1)A standard combination of Qihuang-Zhuyu Formula and Q-TOF/MS was prepared,and 78 compounds were initially identified and postulated by UPLC-Q-TOF/MS.(2)Within 5 days after acute myocardial infarction,IL-1? levels in peripheral blood were elevated in patients;IL-1? levels in peripheral blood were significantly lower in patients treated with Qihuang-Zhuyu Formula compared with those who did not receive the treatment.(3)Primary cardiomyocytes from C57BL/6 mice can release exosomal delivery of lncRNA Lgr6 in the nucleus after hypoxia to inhibit the viability and proliferation of HT-22 cells in mouse hippocampal neurons,trigger NLRP3 Inflammasome signaling,and promote apoptosis.expression in cardiomyocyte exosomes,thereby significantly attenuating this process.(4)Qihuang-Zhuyu Formula can reduce myocardial cell injury and protect cardiac function after myocardial infarction in C57BL/6 mice,reduce lncRNA Lgr6 expression and NLRP3 Inflammasome expression in the brain of myocardial infarction mice,and improve depression-like behavior after myocardial infarction in C57BL/6 mice.(5)Hypoxic cardiomyocyte exosomes further increase post-infarction cardiomyocyte injury and exacerbate depression-like behavior after myocardial infarction in C57BL/6 mice.Meanwhile,hypoxic cardiomyocyte exosomes increased lncRNA Lgr6 expression and NLRP3 Inflammasome expression in the brain of myocardial infarcted mice.This process could be partially blocked using the exosome inhibitor GW4869.CONCLUSION:After acute myocardial infarction,ischemic and hypoxic cardiomyocytes release exosomes carrying lncRNA Lgr6 acting on the nucleoplasm,which is taken up by brain tissue cells(especially cells in the hippocampal region),the delivery of Lgr6 binds to the mRNA of NLRP3 Inflammasome protein and promotes the translational modification of NLRP3 Inflammasome protein,causing an increased apoptosis and decreased cell proliferation,which affected the physiological function of brain parenchyma and triggered depression or depression-like behavior after myocardial infarction.Qihuang-Zhuyu Formula can reduce the expression of IncRNA Lgr6 in brain tissue after myocardial infarction,decrease the formation of NLRP3 Inflammasome,reduce the neuroinflammatory response,and improve depression or depression-like behavior after myocardial infarction.