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Role of Neutrophil-Derived S100B in Acute Myocardial Infarction Patients From the Han Chinese Population.

ABSTRACT: Objective: This study aimed to clarify the novel role of homeostatic calmodulin S100B and determined whether S100B genetic variants affected atherosclerosis progression in acute myocardial infarction (AMI) patients. Methods: Plasma levels of S100B were measured systemically in AMI patients, stable angina pectoris patients, and control subjects. S100B was obtained from the human coronary artery thrombi using a thrombectomy catheter and quantified via immunohistochemical analysis, qRT-PCR and Western blot analyse. We also screened for S100B variations (rs9722, rs9984765, rs2839356, rs1051169, and rs2186358) via direct sequencing, and investigated the relationship between these variants and AMI patients in the Chinese Han population. Results: Plasma S100B levels increased significantly in AMI patients compared to the levels in stable angina pectoris patients and control subjects (119.45 ± 62.46, 161.96 ± 73.30, and 312.91 ± 127.59 pg/ml, respectively). Immunohistochemical staining results showed that S100B expression was increased in the neutrophils of coronary artery thrombi obtained from AMI patients, as compared to that in normal blood clot, and S100B expression was significantly increased in fresh thrombi tissues, as compared to that in organized thrombi tissues. Western blot and qRT-PCR analysis showed that S100B expression increased in coronary artery thrombi, as compared to that in normal blood clots. After pre-treating the neutrophils with siRAGE, the neutrophils migration induced by S100B were abolished through the NFκB-IL1β/IL6 signaling pathway. Compared to their corresponding wild-type genotypes, the S100B rs9722 variant was associated with increased susceptibility to AMI (OR = 1.35, 95%CI: 1.12-1.65, P = 0.02). Individuals with the S100B 9722 A allele had higher plasma S100B levels than those with the G allele in control subjects and AMI patients (141.70 ± 76.69 vs. 107.31 ± 56.05 and 347.13 ± 148.94 vs. 273.05 ± 133.62, respectively). Conclusions: Levels of neutrophil-derived S100B, a novel homeostatic calmodulin, were elevated in the early stages of myocardial infarction. The S100B rs9722 allele was independently associated with AMI patients in the Han Chinese population.

SUBMITTER: Cheng M

PROVIDER: S-EPMC8008063 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMyocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.MethodsUsing a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.ResultsInduction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.ConclusionsOur study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.

Project description:BackgroundAccumulating evidences have shown that miRNAs are directly or indirectly involved in a variety of biological processes, and closely associated with diverse human diseases, including cardiovascular diseases. SNPs locating within pri/pre-miRNA can affect miRNA processing and binding ability of target genes. MiR-27a, miR-26a-1 miR-100, miR-126 and miR-218 were reported to be associated with pathogenesis of myocardial infarction (MI). Here we aimed to evaluate the potential association of five polymorphisms in these pri/pre-miRNAs with individual susceptibility to MI in a Chinese Han population.MethodsGenotyping was performed in 287 MI cases and 646 control subjects using polymerase chain reaction-ligase detection reaction (PCR-LDR) method. The association of these SNPs with MI risk was performed with SPSS software.ResultsIn a logistic regression analysis, we found that AG heterozygote (OR = 0.40, 95% CI = 0.21-0.76, Pa = 0.005) or AA homozygote (OR = 0.40, 95% CI = 0.22-0.75, Pa = 0.004) of pre-miR-27a rs895819 had a reduced susceptibility to MI in comparison with GG homozygote. Similarly, a reduced risk of MI was detected when the AG and AA genotypes were combined (OR = 0.40, 95% CI = 0.22-0.74, Pa = 0.003). However, no significant association between pri-miR-26a-1 pri-miR-100, pri-miR-126 and pri-miR-218 polymorphisms and MI risk was observed under the allelic and established genetic models. Further stratified analysis of pre-miR-27a rs895819 revealed a more significant association of AG + AA genotypes with MI risk among younger, male and smoking subjects. Interestingly, AG and AA genotypes of the rs895819 polymorphism conferred about 0.17 mmol/L and 0.18 mmol/L increase in HDL-C levels compared to GG genotype.ConclusionsOur findings suggest that the pre-miR-27a rs895819 polymorphism is associated with MI susceptibility in the Chinese Han population, which probably due to influence the HDL-C levels.

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Role of Neutrophil-Derived S100B in Acute Myocardial Infarction Patients From the Han Chinese Population.

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