Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction
Background: Depression is a common complication of cardiovascular disease, which deteriorates cardiac function. Shuangxinfang (psycho-cardiology formula, PCF) was reported to alleviate myocardial ischemia injury and improve depression-like behavior. Interestingly, our previous proteomics study predi...
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.832590/full |
| _version_ | 1811342812791177216 |
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| author | Yize Sun Zheyi Wang Jiqiu Hou Jinyu Shi Zhuoran Tang Chao Wang Haibin Zhao |
| author_facet | Yize Sun Zheyi Wang Jiqiu Hou Jinyu Shi Zhuoran Tang Chao Wang Haibin Zhao |
| author_sort | Yize Sun |
| collection | DOAJ |
| description | Background: Depression is a common complication of cardiovascular disease, which deteriorates cardiac function. Shuangxinfang (psycho-cardiology formula, PCF) was reported to alleviate myocardial ischemia injury and improve depression-like behavior. Interestingly, our previous proteomics study predicted that the protein S100A9 appeared as an important target, and macrophage/microglial inflammation might be involved in the process of PCF improving depression induced by acute myocardial infarction (AMI). This study aims to validate the proteomics results.Methods: AMI rat models were established in vivo, followed by the administration of PCF or ABR-215757 (also named paquinimod, inhibiting S100A9 binding to TLR4) for 5 days. Forced swimming test (FST) and open field test (OFT) were applied to record depression-like behavior, and echocardiography was employed to evaluate cardiac function. Morphological changes of cardiomyocytes were assessed by HE staining and TUNEL staining on day 7 after cardiac surgery, as well as Masson trichrome staining on day 21. Hippocampal neurogenesis was determined by Nissl staining, while 5-hydroxytryptamine (5-HT), tryptophan/kynurenine ratio, and brain-derived neurotrophic factor (BDNF) in the hippocampus were analyzed as biochemical indicators of depression. We employed RT-qPCR, western blotting, and immunofluorescence to detect the expression of pathway-related genes and proteins. Myocardial and hippocampal expression of inflammatory factors were performed by ELISA. The activation of macrophage and microglia was assessed via immunoreaction using CD68 and Iba1, respectively. For in vitro confirmation, BV2 cells were primed with recombinant protein S100A9 and then treated with PCF serum or ferulic acid to determine alterations in microglial inflammation.Results: Rats in the AMI group showed heart function deterioration and depression-like behavior. Coronary ligation not only brought about myocardial inflammation, cell apoptosis, and fibrosis but also reduced the neurogenesis, elevated the tryptophan/kynurenine ratio, and decreased the content of 5-HT. PCF could ameliorate the pathological and phenotypic changes in the heart and brain and inhibit the expression of the S100A9 protein, the activation of the microglial cell, and the secretion of IL-1β and TNF-α raised by AMI. ABR-215757 showed therapeutic effect and molecular biological mechanisms similar to PCF. Treatment with PCF serum or ferulic acid in vitro was proved to efficiently block the hyperactivation of BV2 cells and increment of cytokine contents induced by recombinant protein S100A9.Conclusion: We identify S100A9 as a novel and potent regulator of inflammation in both the heart and brain. Macrophage/microglia inflammation mediated by S100A9 is considered a pivotal pathogenic in depression after AMI and a major pathway for the treatment of PCF, suggesting that PCF is a promising therapeutic candidate for psycho-cardiology disease. |
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| spelling | doaj.art-0e8fe87b80ca4d32942f30ab96f095b72022-12-22T02:33:37ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.832590832590Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial InfarctionYize Sun0Zheyi Wang1Jiqiu Hou2Jinyu Shi3Zhuoran Tang4Chao Wang5Haibin Zhao6Third Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, ChinaQilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, ChinaOriental Hospital, Beijing University of Chinese Medicine, Beijing, ChinaOriental Hospital, Beijing University of Chinese Medicine, Beijing, ChinaThird Affiliated Hospital, Beijing University of Chinese Medicine, Beijing, ChinaOriental Hospital, Beijing University of Chinese Medicine, Beijing, ChinaOriental Hospital, Beijing University of Chinese Medicine, Beijing, ChinaBackground: Depression is a common complication of cardiovascular disease, which deteriorates cardiac function. Shuangxinfang (psycho-cardiology formula, PCF) was reported to alleviate myocardial ischemia injury and improve depression-like behavior. Interestingly, our previous proteomics study predicted that the protein S100A9 appeared as an important target, and macrophage/microglial inflammation might be involved in the process of PCF improving depression induced by acute myocardial infarction (AMI). This study aims to validate the proteomics results.Methods: AMI rat models were established in vivo, followed by the administration of PCF or ABR-215757 (also named paquinimod, inhibiting S100A9 binding to TLR4) for 5 days. Forced swimming test (FST) and open field test (OFT) were applied to record depression-like behavior, and echocardiography was employed to evaluate cardiac function. Morphological changes of cardiomyocytes were assessed by HE staining and TUNEL staining on day 7 after cardiac surgery, as well as Masson trichrome staining on day 21. Hippocampal neurogenesis was determined by Nissl staining, while 5-hydroxytryptamine (5-HT), tryptophan/kynurenine ratio, and brain-derived neurotrophic factor (BDNF) in the hippocampus were analyzed as biochemical indicators of depression. We employed RT-qPCR, western blotting, and immunofluorescence to detect the expression of pathway-related genes and proteins. Myocardial and hippocampal expression of inflammatory factors were performed by ELISA. The activation of macrophage and microglia was assessed via immunoreaction using CD68 and Iba1, respectively. For in vitro confirmation, BV2 cells were primed with recombinant protein S100A9 and then treated with PCF serum or ferulic acid to determine alterations in microglial inflammation.Results: Rats in the AMI group showed heart function deterioration and depression-like behavior. Coronary ligation not only brought about myocardial inflammation, cell apoptosis, and fibrosis but also reduced the neurogenesis, elevated the tryptophan/kynurenine ratio, and decreased the content of 5-HT. PCF could ameliorate the pathological and phenotypic changes in the heart and brain and inhibit the expression of the S100A9 protein, the activation of the microglial cell, and the secretion of IL-1β and TNF-α raised by AMI. ABR-215757 showed therapeutic effect and molecular biological mechanisms similar to PCF. Treatment with PCF serum or ferulic acid in vitro was proved to efficiently block the hyperactivation of BV2 cells and increment of cytokine contents induced by recombinant protein S100A9.Conclusion: We identify S100A9 as a novel and potent regulator of inflammation in both the heart and brain. Macrophage/microglia inflammation mediated by S100A9 is considered a pivotal pathogenic in depression after AMI and a major pathway for the treatment of PCF, suggesting that PCF is a promising therapeutic candidate for psycho-cardiology disease.https://www.frontiersin.org/articles/10.3389/fphar.2022.832590/fullShuangxinfangtraditional Chinese medicineacute myocardial infarctionepressive disorderS100A9inflammation |
| spellingShingle | Yize Sun Zheyi Wang Jiqiu Hou Jinyu Shi Zhuoran Tang Chao Wang Haibin Zhao Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction Frontiers in Pharmacology Shuangxinfang traditional Chinese medicine acute myocardial infarction epressive disorder S100A9 inflammation |
| title | Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction |
| title_full | Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction |
| title_fullStr | Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction |
| title_full_unstemmed | Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction |
| title_short | Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction |
| title_sort | shuangxinfang prevents s100a9 induced macrophage microglial inflammation to improve cardiac function and depression like behavior in rats after acute myocardial infarction |
| topic | Shuangxinfang traditional Chinese medicine acute myocardial infarction epressive disorder S100A9 inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.832590/full |
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