Shuangxinfang Prevents S100A9-Induced Macrophage/Microglial Inflammation to Improve Cardiac Function and Depression-Like Behavior in Rats After Acute Myocardial Infarction

Abstract

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.

Identification of key genes and biological pathways in chronic obstructive pulmonary disease using bioinformatics and next generation sequencing data analysis

“…LMNA (lamin A/C) [676], VCAM1 [986], PHGDH (phosphoglycerate dehydrogenase) [1100], S100A9 [1045], FKBP5 [1046], FHL2 [1003], ATF3 [85] and MPO (myeloperoxidase) [1084] plays an important role in the development of obesity. LMNA (lamin A/C) [1127], VCAM1 [1110], S100A9 [239], TP63 [1125], JUND (JunD proto-oncogene, AP-1 transcription factor subunit) [1118], FHL2 [1132], ATF3 [93], BPI (bactericidal permeability increasing protein) [1178], DYSF (dysferlin) [1180], MPO (myeloperoxidase) [1195] and ALPL (alkaline phosphatase, biomineralization associated) [1194] were reported to be associated with the prognosis of heart problems. LMNA (lamin A/C) [1313], VCAM1 [1299], PHGDH (phosphoglycerate dehydrogenase) [1382], S100A9 [81], TP63 [1312], FHL2 [1318], ATF3 [80] and MPO (myeloperoxidase) [1375] have been identified as a key genes in idiopathic pulmonary fibrosis.…”

The role of immune inflammatory response and inflammatory infiltrates in major depression disorder and atopic dermatitis: new insights from machine learning

“…This is associated with the impairment of the epidermal barrier in specific dermatitis, suggesting that S100A9 may be a potential target for treating specific dermatitis(Zhao et al, 2020). S100A9 is also considered a novel and effective regulator of brain inflammation because it can mediate inflammation in microglia/macrophages, ultimately leading to MDD(Sun et al, 2022). These results suggest that as an inducer of inflammation, S100A9 can participate in the pathogenic mechanisms of both AD and MDD.…”

Expression pattern and diagnostic value of ferroptosis-related genes in acute myocardial infarction

“…It is reported that ITGAM is a key immune-related gene, which is significantly increased in blood samples of patients with AMI ( 25 ). S100A9 and S100A12 are up-regulated in the process of AMI and can induce macrophage/microglia inflammation ( 26 , 27 ). Shuangxinfang (psycho-cardiology formula, PCF) could inhibit this process and improve the heart function of mice with myocardial infarction ( 26 ).…”

“…S100A9 and S100A12 are up-regulated in the process of AMI and can induce macrophage/microglia inflammation ( 26 , 27 ). Shuangxinfang (psycho-cardiology formula, PCF) could inhibit this process and improve the heart function of mice with myocardial infarction ( 26 ). TREM-1 is a receptor of immunoglobulin superfamily, which has been proved to induce and amplify inflammation in the progress of acute and chronic diseases ( 28 ).…”