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Myocardial ischemia injury activates neuronal discharge, while being ameliorated by EA treatment. (a) Representative electrophysiological images from different groups. (b) Cell numbers and cell types for the discharged cells. (c) Discharge frequency in different groups. Data were presented as mean and SD. P∗∗<0.01 compared with sham control. P##<0.01 compared with model.
Source publication
Mechanisms for electroacupuncture (EA) in disease treatments are still enigmatic. Here, we studied whether hippocampus was involved in the protection of EA stimulation on myocardial ischemia injury. Acute myocardial ischemia (AMI) model was produced. EA stimulation at heart meridian from Shenmen (HT7) to Tongli (HT5) was applied to rats 3 times a d...
Citations
... The acupoints were marked and the electroacupuncture operation was performed as described in previous studies. 25,26,28,29 Briefly, electroacupuncture stimulation was applied to the heart meridian at the Shenmen (HT7)-Tongli (HT5) segment using an electroacupuncture stimulator instrument (Hwato SDZ-V type, Suzhou Medical Supplies Co. Ltd., Suzhou, China). Three sterile acupuncture needles (0.30 mm × 25 mm, Suzhou Medical Supplies Co., Ltd., Suzhou, China) were inserted bilaterally into the Shenmen (HT7)-Tongli (HT5) segment at a depth of 4 mm in each acupoint. ...
Objective:
To verify the hypothesis that electroacupuncture inhibits the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis regulating the expression of glial fibrillary acidic protein (GFAP) in the hippocampus of acute myocardial ischemia (AMI) rats.
Methods:
Sixty-six healthy male Sprague-Dawley rats were randomly divided into five groups: Sham, AMI (Model), electroacupuncture at Shenmen (HT7)-Tongli (HT5) segment (EA), non-acupoint electroacupuncture (Control), and Model + corticosterone (Model + CORT). AMI was induced occlusion of the left anterior descending coronary artery, followed by 3 d of electroacupuncture at Shenmen (HT7)-Tongli (HT5) segment. In the Control group, electroacupuncture was applied at points lying 5 and 10 mm from the base of the tail. The AMI + CORT group was injected with CORT (20 mg/kg) in saline. Hemorheology, electrocardiography (ECG), hematoxylin and eosin staining, and expression of glycogen phosphorylase BB (GPBB) and heart-type fatty acid-binding protein (H-FABP) were used to assess cardiac function. The effects of adrenocorticotropic hormone (ACTH) and CORT were evaluated by enzyme-linked immunosorbent assay. Protein expression in the Sham and Model groups were screened by tandem mass tag-based quantitative proteomics analysis. Protein expression was evaluated by Western blotting (vimentin and GFAP) and immunofluorescence staining (GFAP).
Results:
Compared with the Sham group, the hemorheology indicators, heart rate, ECG-ST segment elevation, and GPBB and H-FABP levels were higher in Model rats. The EA group showed reductions in these indicators compared with the Model group. Similarly, in Model rats, the expression of ACTH and CORT were significantly increased compared with the Sham group. The EA group also showed reduced expression of ACTH and CORT. Importantly, proteomics analysis showed that vimentin was differentially expressed in Model rats. Compared with the Sham group, vimentin and GFAP expression in the hippocampus was increased in the Model group but decreased in the AMI + EA group. Additionally, intraperitoneal injection of CORT aggravated the expression of GPBB, H-FABP and GFAP.
Conclusions:
Our results suggested that electroacupuncture may protect against cardiac injury induced by AMI through regulation of HPA axis hyperactivity, and that hippocampal GFAP may play an important role in the regulation.
... Previous studies found that activation of NR4A2 was an adaptive response to ischemia-induced apoptosis in cardiomyocytes (50). Interestingly, cardiomyocytes after myocardial infarction undergo significant apoptosis due to ischemia (51). When ischemia persists, cells within the infarcted region initiate autophagic mechanisms to slow the progression of cardiomyocyte death (52). ...
Background
Myocardial infarction is a well-established severe consequence of coronary artery disease. However, the lack of effective early biomarkers accounts for the lag time before clinical diagnosis of myocardial infarction. The present study aimed to predict critical genes for the diagnosis of MI by immune infiltration analysis and establish a nomogram.
Methods
Gene microarray data were downloaded from Gene Expression Omnibus (GEO). Differential expression analysis, single-cell sequencing, and disease ontology (DO) enrichment analysis were performed to determine the distribution of Differentially Expressed Genes (DEGs) in cell subpopulations and their correlation with MI. Next, the level of infiltration of 16 immune cells and immune functions and their hub genes were analyzed using a Single-sample Gene Set Enrichment Analysis (ssGSEA). In addition, the accuracy of critical markers for the diagnosis of MI was subsequently assessed using receiver operating characteristic curves (ROC). One datasets were used to test the accuracy of the model. Finally, the genes with the most diagnostic value for MI were screened and experimentally validated.
Results
335 DEGs were identified in GSE66360, including 280 upregulated and 55 downregulated genes. Single-cell sequencing results demonstrated that DEGs were mainly distributed in endothelial cells. DO enrichment analysis suggested that DEGs were highly correlated with MI. In the MI population, macrophages, neutrophils, CCR, and Parainflammation were significantly upregulated compared to the average population. NR4A2 was identified as the gene with the most significant diagnostic value in the immune scoring and diagnostic model. 191 possible drugs for the treatment of myocardial infarction were identified by drug prediction analysis. Finally, our results were validated by Real-time Quantitativepolymerase chain reaction and Western Blot of animal samples.
Conclusion
Our comprehensive in silico analysis revealed that NR4A2 has huge prospects for application in diagnosing patients with MI.
... EA may also have a beneficial effect on ischemic heart disease such as MI by reducing lipid peroxidation; promoting energy metabolism, myocardial oxygen demand, and myocardial enzyme activity; and altering cellular ultrastructure. However, its mechanism of action is not yet clear [43][44][45]. ...
Acute myocardial infarction (AMI) is the most severe form of coronary heart disease caused by ischemia and hypoxia. The study is aimed at investigating the role of neuropeptides and the mechanism of electroacupuncture (EA) in acute myocardial infarction (AMI) treatment. Compared with the normal population, a significant increase in substance P (SP) was observed in the serum of patients with AMI. PGI2 expression was increased in the SP-treated AMI mouse model, and TXA2 expression was decreased. And PI3K pathway-related genes, including Pik3ca, Akt, and Mtor, were upregulated in myocardial tissue of SP-treated AMI patients. Human cardiomyocyte cell lines (HCM) treated with SP increased mRNA and protein expression of PI3K pathway-related genes (Pik3ca, Pik3cb, Akt, and Mtor). Compared to MI control and EA-treated MI rat models, Myd88, MTOR, Akt1, Sp, and Irak1 were differentially expressed, consistent with in vivo and in vitro studies. EA treatment significantly enriched PI3K/AKT signaling pathway genes within MI-associated differentially expressed genes (DEGs) according to Kyoto Encyclopedia of Genes and Genomes (KEGG). Furthermore, it was confirmed by molecular docking analysis that PIK3CA, AKT1, and mTOR form stable dockings with neuropeptide SP. PI3K/AKT pathway activity may be affected directly or indirectly by EA via SP, which corrects the PGI2/TXA2 metabolic imbalance in AMI. MI treatment is now better understood as a result of this finding.
... The data demonstrated that SP could increase food intake following heart failure. Reduction of heart rate is an important functional index of heart failure (33). The present study used an ECG to monitor heart function. ...
The function of substance P (SP) in myocardial ischemia is well understood, but its effects on congestive heart failure are unclear. The present study aimed to use in vitro and in vivo approaches to investigate the effects of SP on doxorubicin‑induced cardiomyocyte injury. Pathological changes, apoptosis, cardiomyocyte ultrastructure and molecular mechanisms were evaluated in vitro and in vivo. The effects of SP on cell viability of H9c2 myocardial cells were evaluated using the Cell Counting Kit‑8 and flow cytometry. B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), Beclin‑1 and microtubule‑associated protein 1A/1B‑light chain 3 (LC3) were detected by western blotting. Heart failure in rats was established by intraperitoneal injection of doxorubicin. The in vitro data demonstrated that SP at concentrations of 1 µg/ml inhibited doxorubicin‑induced apoptosis of H9c2 cells. Administration of doxorubicin reduced Bcl‑2, Beclin‑1 and LC3 expression levels in H9c2 cells, while having no effect on Bax levels. Administration of SP to these doxorubicin‑treated cells did not affect Bcl‑2 or Bax expression, but further reduced Beclin‑1 while inhibiting the reduction in LC3 expression. In vivo, food intake was significantly increased in rats in the SP group compared with the model group. Cardiomyocytes in the heart‑failure group underwent dysfunctional autophagy as ascertained by transmission electron microscopy. Compared with the heart‑failure group, these pathological changes, including loss of striations and vacuolation, were inhibited by SP treatment, which promoted Bax expression, reduced Beclin‑1 expression and inhibited the reduction in LC3 expression. Taken together, SP reduced cardiomyocyte apoptosis in doxorubicin‑induced cardiomyocyte injury, likely by promoting autophagy, which suggested that SP is a potential therapeutic target for doxorubicin‑induced heart failure.
... The incidence rate of cardiovascular disease is soaring worldwide, accompanied by high morbidity from ischemic heart disease. Coronary atherosclerosis (Gimelli et al., 2017), in ammation (Bai et al., 2018), hypotension (Wu et al., 2015) and coronary artery spasm (Kuczkowski, 2006) have been involved in the development of ischemic heart disease. Myocardial ischemia can be treated by drugs, interventional therapy and surgery alone or in combination. ...
Aim of the study: Salvianolic acid B(Sal B) as a natural compound extracted from Salvia miltiorrhiza, has been extensively used to protect cardiomyocytes from myocardial ischemia. Although Sal B has shown evident effects on cardiovascular diseases, the detailed mechanism is still unclear as yet. Herein, we intended to explorethe protective effects of Sal B on myocardial ischemic injury and the underlying mechanism.
Methods and Results: Western blotting, immunofluorescence assay, flow cytometry and lentiviral transfection were performed. The mice with myocardial ischemic injury were intravenously given 10 mg/kg Sal B once daily for seven days, and then H9c2 cells were treated with Sal B (20, 40, 80 μmol/L). Sal B treatment protected cardiomyocytes from myocardial ischemia through relieving apoptosis. Transmission electron microscopy and fluorescence microscopy exhibited that Sal B significantly increased autophagic lysosomes and vacuoles in H9c2 cells. Administration with Sal B significantly up-regulated the expressions of autophagy-related factors such as LC3, Atg5 and Beclin 1 in H9c2 cells and myocardial tissues. The beneficial autophagic changes induced by Sal B were abrogated through pharmacological inhibition.
Conclusions: This study provides a molecular mechanism by which Sal B potently inhibits apoptosis and oxidative stress upon myocardial ischemia by activating the AMPK-autophagy pathway. Sal B is a potential agent for treating myocardial ischemia.
... Immunohistochemistry was conducted as previously described. [14] Briefly, the tissues were fixed in 10% formalin solution, preserved in wax blocks, and sectioned. After heat recovery, the sections were incubated with primary antibodies against msi1 (1:200, ab52865, abcam) and numb (1:500, TA501614, ORIGENE). ...
The expression of tumor stem cell markers musashi1 (msi1) and numb in brain metastases were detected to explore their roles in the development of brain metastases.
A total of 51 cases of brain metastasis, 29 cases of primary tumor and 15 cases of normal brain tissue were selected. Immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR) were used to detect msi1 and numb expression at the protein and mRNA levels. Correlation between msi1 and numb in brain metastases were evaluated.
Immunohistochemistry and RT-PCR showed that no significant difference in the expression of msi1 and numb between brain metastases and primary tumors was observed (P > .05); the expression of msi1 and numb in brain metastases was significantly higher than that in normal brain tissues (P < .05); and the expression of msi1 and numb in primary tumors was significantly higher than that in normal brain tissues (P < .05). In general, the expression of msi1 gene was negatively correlated with the expression of numb at mRNA level by Pearson correlation analysis (r = −0.345, P < .05). Additionally, the expression of msi1 and numb in brain metastases was not related to gender, age, and tissue origin (P > .05).
Msi1 is highly expressed in brain metastases and primary tumors, while numb is lowly expressed in brain metastases and primary tumors; msi1 and numb are negatively correlated in brain metastases, suggesting that msi1 and numb may have regulatory mechanisms in the development of brain metastases.
... And cognitive dysfunction due to AMI in adult mice was correlated with decreases in reactive gliosis and neurogenesis in the hippocampus [11]. In our previous work, we showed that EA alleviates AMI in the hippocampus via regulation of the autonomic nervous system speci cally through the synergistic regulation of the sympathetic and vagus nerves by the hippocampal paraventricular nucleus and solitary tract nucleus, respectively [12][13][14]. These results suggest that the hippocampus is an important central brain structure mediating the positive effects of EA following AMI. ...
... The hippocampus is a critical brain structure for memory and cognition as well as cardiovascular function. Cognitive de cits have been reported in patients with cardiovascular disease [36][37][38]and heart failure patients exhibit damage to the hippocampus [39,40].We previously showed that the mechanism by which acupuncture alleviates AMI-induced damage in the hippocampus is through synergistic action of the paraventricular nucleus, which regulate the sympathetic nerve and the solitary tract nucleus, which regulates the vagus nerve [12][13][14]. ...
Background: Electroacupuncture (EA) alleviates acute myocardial ischemia (AMI) by regulating some brain areas, including hippocampus. The locus coeruleus (LC) is the main source of norepinephrine (NE) in the brain, including the hippocampus, and regulates cardiovascular function. The aim of the present work was to assess whether LC mediates the positive effects of EA in AMI by altering gene expression levels in the hippocampus. We addressed this in the present study by hippocampus transcriptome profiling in a rat model of AMI following EA treatment.
Results: Myocardial injury markers (ischemia-modified albumin, homocysteine and lipoprotein- associated phospholipase A2) in the serum were downregulated in EA (P<0.05) compared to the M group and upregulated in E+L group (P<0.05) compared to E group. RNA sequencing analysis of the hippocampus revealed that the downregulation of 27 genes in M vs S as well as upregulation of 40 genes in M vs S were reversed by EA. These differentially expressed genes, which were validated by quantitative real-time PCR, were enriched in 20 Kyoto Encyclopedia of Genes and Genomes pathways related to glycerolipid, glycerophospholipid, and arachidonic acid metabolism as well asnervous system function (glutamatergic, cholinergic, serotonergic, GABAergic synapses).
Conclusions: LC mediates the beneficial effects of EA on AMI-induced injury may be related to the observed transcriptional regulations in the hippocampus. These results provide molecular-level evidence for the therapeutic efficacy of EA in the treatment of AMI.
... e locus coeruleus (LC) is the principal site of NE synthesis in the brain, and most noradrenergic neurons in the brain are concentrated in the LC and function mainly in the regulation of cardiovascular activity [20][21][22]. We previously demonstrated that AMI could activate relevant central nuclei to different degrees, and EA could ameliorate this phenomenon, thereby providing further evidence that the heart and brain are closely related [23,24]. ...
... With reference to a previous study [23], the "Shenmen (HT7)-Tongli (HT5)" segment in the Shaoyin heart meridian of the hand was identified for electrical stimulation according to the standard of acupuncture and moxibustion point localization in rats 1 day after successful ligation. EA was performed as follows: three 0.30 mm × 25 mm sterile acupuncture and moxibustion needles were inserted into the bilateral "Shenmen"-"Tongli" segments. ...
The locus coeruleus (LC) is closely linked with cardiovascular disease. However, whether it mediates the alleviating effect of electroacupuncture (EA) on acute myocardial ischemia (AMI) remains unclear. A rat model of myocardial ischemia was established through occlusion of the left anterior descending coronary artery. Multichannel in vivo recording and other techniques were used to assess neurons in the LC, norepinephrine (NE) and dopamine (DA) levels in central and myocardial tissue, serum levels of inflammatory factors, and cardiac function. After induction of AMI, LC neuron activity increased and the central NE concentrations increased, while those of DA decreased. Moreover, the serum levels of high-sensitivity C-reactive protein (hs-CRP) increased, whereas those of interleukin-10 (IL-10) decreased. However, these effects were reversed by EA. Additionally, LC lesioning affected NE and DA levels in myocardial tissue and weakened the antimyocardial ischemic effect of EA. Collectively, our results indicated that LC is closely related to AMI and plays an important role in the antimyocardial ischemic effect of EA. This mechanism may be related to inhibition of LC neuron activity by EA, which inhibits the release of large amounts of hs-CRP and promotes that of IL-10 in the serum. Besides, after LC lesioning, EA may improve cardiac function by inhibiting the release of large amounts of NE and promoting the release of DA in myocardial tissue.
... DAB was used to color the staining. The imaging and density analysis were following previous description [18] by using ImageJ software. At least 4 fields in each image were analyzed. ...
Background
Protective effects of reduced beta 2 glycoprotein I (Rβ2GPI) against vascular injury of diabetes mellitus have been extensively investigated. However, the effects of Rβ2GPI on liver injury in diabetic animals have not been reported.
Material/Methods
A diabetic rat model of was produced by systemic injection of streptozotocin (STZ). Rats were divided into a normal control group, a model group, and an Rβ2GPI treatment group (N=6 in each group). After treatments, blood serum and liver tissue were collected to test the protection of Rβ2GPI. AMP-activated protein kinase (AMPK) was detected by immunohistochemistry and Western blotting.
Results
Our results revealed that Rβ2GPI reduced blood glucose, serum creatinine, and urea nitrogen levels, as well as serum inflammation cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-a and C-reactive protein in the diabetic rats. Importantly, Rβ2GPI prevented liver injury in the diabetic rats as confirmed by hematoxylin-eosin (H&E) staining, alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase. Reactive oxygen species (ROS) were promoted by diabetic modeling and were attenuated by Rβ2GPI administration. Moreover, Rβ2GPI significantly reduced liver catalase, malondialdehyde, and superoxide dismutase levels in the diabetic rats. Rβ2GPI reduced liver glycolipid storage in STZ diabetic rats. Both immunohistochemistry and Western blotting demonstrated that Rβ2GPI promoted AMPK phosphorylation in the diabetic rats.
Conclusions
Our data proved that Rβ2GPI prevented liver injury in diabetic rats, likely through activating the AMPK signaling pathway.
... Electroacupuncture (EA) improves the symptoms of myo- cardial ischemia, modulates autonomic nervous system ac- tivity, and reverses the effect of myocardial ischemia on the hippocampal CA1 region ( Wu et al., 2015). However, the pathways involved in alleviating myocardial ischemic dam- age are unclear. ...
... Three days before artery ligation, the hippocampal CA1 re- gion was lesioned using a previously described method ( Wu et al., 2015). Briefly, kainic acid, 1 mg/L, (Sigma-Aldrich, St. Louis, MO, USA) was injected into the hippocampal CA1 region bilaterally at bregma ?4.16 mm, lateral 2.8 mm, depth 2.8-3.0 mm, according to the rat brain atlas (Paxinos and Watson, 2009) (Additional Figure 1A, B). ...
The hippocampus is involved in the regulation of the autonomic nervous system, together with the hypothalamus and brainstem nuclei, such as the paraventricular nucleus and nucleus tractus solitarius. The vagus nerve-nucleus tractus solitarius pathway has an important role in cardiovascular reflex regulation. Myocardial ischemia has been shown to cause changes in the autonomic nervous system, affecting the dynamic equilibrium of the sympathetic and vagal nerves. However, it remains poorly understood how the hippocampus communicates with brainstem nuclei to regulate the autonomic nervous system and alleviate myocardial ischemic tissue damage. A rat model of acute myocardial ischemia (AMI) was made by ligating the left anterior descending branch of the coronary artery. Three days before ischemia, the hippocampal CA1 region was damaged. Then, 3 days after ischemia, electroacupuncture (EA) at Shenmen (HT7)-Tongli (HT5) was performed (continuous wave, 1 mA, 2 Hz, duration of 30 minutes). Cluster analysis of firing patterns showed that one type of neuron was found in rats in the sham and AMI groups. Three types of neurons were observed in the AMI + EA group. Six types of neurons were found in the AMI + EA + Lesion group. Correlation analysis showed that the frequency of vagus nerve discharge in each group was negatively correlated with heart rate (HR) (P < 0.05, r = -0.424), and positively correlated with mean arterial pressure (MAP) (P < 0.05, r = 0.40987) and the rate-pressure product (RPP) (P < 0.05, r = 0.4252). The total frequency of the nucleus tractus solitarius discharge in each group was positively correlated with vagus nerve discharge (P < 0.01, r = 0.7021), but not with hemodynamic index (HR: P > 0.05, r = -0.03263; MAP: P > 0.05, r = -0.08993; RPP: P > 0.05, r = -0.03263). Some neurons (Neuron C) were negatively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA group (vagus nerve discharge: P < 0.05, r = -0.87749; HR: P < 0.01, r = -0.91902; MAP: P < 0.05, r = -0.85691; RPP: P < 0.01, r = -0.91902). Some neurons (Neurons C, D and E) were positively correlated with vagus nerve discharge, HR, MAP and RPP in the AMI + EA + Lesion group (vagus nerve discharge: P < 0.01, r = 0.8905, P < 0.01, r = 0.9725, P < 0.01, r = 0.9054; HR: P < 0.01, r = 0.9347, P < 0.01, r = 0.9089, P < 0.05, r = 0.8247; MAP: P < 0.05, r = 0.8474, P < 0.01, r = 0.9691, P < 0.01, r = 0.9027; RPP: P < 0.05, r = 0.8637, P < 0.01, r = 0.9407, P < 0.01, r = 0.9027). These findings show that the hippocampus-nucleus tractus solitarius-vagus nerve pathway is involved in the cardioprotective effect of EA at the heart meridian. Some interneurons in the nucleus tractus solitarius may play a particularly important role in the cardiomodulatory process.
