Acute myocardial infarction (AMI) is a condition triggered by an inflammatory process that seriously affects human health. Calcium-sensing receptor (CaSR) in T lymphocytes is involved during the inflammation reaction. However, the relationship between them is not very clear. In this study, we collected human peripheral blood T lymphocytes from patients with AMI and in different stages of percutaneous coronary intervention (PCI) (at the onset of AMI, the first day after PCI (PCI-1), PCI-3, and PCI-5) to study the CaSR and NF-κB pathway protein expression, cytokine release and T cell apoptosis. The results showed that the expressions of CaSR, P-p65, Caspase-12, and the secretions of Th-1 and Th-2 type cytokines were increased at the onset of AMI, especially on the PCI-1. Meanwhile, the apoptosis rate of CD3+, CD4+ and CD8+ T lymphocytes also increased. However, from PCI-3, all the indicators began to decline. In addition, we also found that positive CaSR small interfering RNA (siRNA) transfection in T lymphocytes and NF-κB pathway blocker Bay-11-7082 reversed the increased expressions of CaSR, P-p65, Caspase-12, reduced the secretions of Th-1 and Th-2 type cytokines, and decreased T lymphocytes apoptosis rate not only in the AMI patients but also in the normal controls. All of these results indicated that CaSR in the human peripheral blood T lymphocytes were involved in the AMI onset and progression, which probably was related to the NF-κB pathway. Our study demonstrated the relationship between AMI and CaSR, and will provide new effective prevention theory and new targets for drug treatment.
Cardiovascular disease is the leading cause of human mortality and morbidity worldwide. Atherosclerosis (AS) is the underlying pathological responsible in most acute and severe cardiovascular diseases including myocardial infarction and stroke. However, current drugs applied to the treatment of AS are not clinically effective, and there is a large residual risk of cardiovascular disease and multiple side effects. Increasing evidence supports a close relationship between microorganisms and the incidence of AS. Recent data have shown that probiotics can improve multiple key factors involved in the development and progression of AS, including cholesterol metabolism imbalance, endothelial dysfunction, proinflammatory factor production, macrophage polarization, intestinal flora disturbance, and infection with pathogenic microorganisms, and therefore probiotics have attracted great interest as a novel potential “medicine”. This review is aimed at summarizing the effects of probiotics on various influencing factors, and providing valuable insights in the search for early prevention and potential therapeutic strategies for AS.
Ischemia-reperfusion (I/R) injury caused by acute myocardial infarction (AMI) can initiate a strong inflammatory response. Polymorphonuclear cells (PMNs) are the most important inflammatory cells. Our previous studies found that the calcium-sensing receptor (CaSR) regulates the proinflammatory effects of PMNs. However, the role and mechanism of CaSR-regulated PMNs in I/R injury remain uncertain. A rat AMI model was developed in this study and showed that the expression of CaSR on PMNs increased in AMI; however, the levels of Bcl-xl and SOD in myocardial tissue decreased, while Bax and MDA levels increased. Then, after coculture with CaSR-stimulated PMNs, the expression of Bcl-xl in cardiomyocytes significantly increased, Bax expression and the apoptotic rate decreased, and ROS production was significantly inhibited. At the same time, the cardiomyocyte damage caused by hypoxia-reoxygenation was reduced. Furthermore, we found that exosomes derived from PMNs could be taken up by cardiomyocytes. Additionally, the exosomes secreted by CaSR-stimulated PMNs had the same effect on cardiomyocytes as CaSR-stimulated PMNs, while the increased phosphorylation level of AKT in cardiomyocytes could be revered by AKT transduction pathway inhibitors. Subsequently, we identified the exosomes derived from CaSR-stimulated PMNs by second-generation sequencing technology, and increased expression of lncRNA ENSRNOT00000039868 was noted. The data show that this lncRNA can prevent the hypoxia-reoxygenation injury by upregulating the expression of PDGFD in cardiomyocytes. In vivo, exosomes from CaSR-stimulated PMNs played a significant role against AMI and reperfusion injury in myocardial tissue. Thus, we propose that exosomes derived from CaSR-stimulated PMNs can reduce I/R injury in AMI, and this effect may be related to the AKT signaling pathway.
The calcium-sensing receptors (CaSRs) play an important role in many tissues and organs that are involved in inflammatory reactions. Peripheral blood polymorphonuclear neutrophils (PMNs) are important inflammatory cells. However, the expression and functions of CaSR in peripheral blood PMNs are still not reported. In this study, we collected rat peripheral blood PMNs to observe the relationship between CaSR and PMNs. From the results, we found first that the CaSR protein was expressed in PMNs, and it increased after PMNs were activated with fMLP. In addition, CaSR activator cincalcet promoted the expression of CaSR and P-p65 (NF-κB signaling pathway protein) and Bcl-xl (antiapoptosis protein), and it increased the secretion of interleukin-6 (IL-6) and myeloperoxidase (MPO); meanwhile, it decreased proapoptosis protein Bax expression and the production of IL-10 and reactive oxygen species (ROS). At the same time, cincalcet also decreased the PMN apoptosis rate analyzed by flow cytometry. However, CaSR inhibitor NPS-2143 and NF-κB signaling pathway inhibitor PDTC reverse the results cited earlier. All of these results indicated that CaSR can regulate PMN functions and status to play a role in inflammation, which is probably through the NF-κB signaling pathway.
Acute myocardial infarction (AMI) is a disease associated with inflammation. T lymphocytes are involved by secreting cytokines and inflammatory factors. In our previous study, it was found that the T lymphocytes exhibited certain functional changes, the onset of which was induced by modulating calcium-sensing receptor (CaSR) in AMI. In the present study, western blotting was used to verified the expression of T lymphocyte CaSR and pathway proteins, including phosphorylated extracellular signal-regulated kinase (P-ERK)1/2 and phosphorylated c-Jun N-terminal kinase (P-JNK), and used cytometric bead array to detect the secretion of interleukin (IL)-4, IL-6, IL-10 and tumor necrosis factor (TNF)-α in AMI onset, the results demonstrated that they were all increased. In addition, the expression of T lymphocyte pathway proteins, including P-ERK1/2 and P-JNK, and the secretion of IL-4, IL-6, IL-10 and TNF-α decreased after T lymphocytes being transfected by CaSR small interfering RNA. By contrast, the neonatal mouse cardiomyocytes under hypoxia and hypoxia/re-oxygenation exhibited ultrastructural damage, increased apoptosis, increased production of lactate dehydrogenase (LdH) and malondialdehyde, and reduced superoxide dismutase; these indicators changed extensively when cardiomyocytes were co-cultured with T lymphocytes. However, the effects were reversed when the cardiomyocytes were co-cultured with CaSR-silenced T lymphocytes. These results indicated that CaSR may modulate T lymphocytes to release cytokines through mitogen-activated protein kinase pathways and affect cardiomyocyte injury. The relationship between AMI and T lymphocyte CaSR is reciprocal.
Coronary heart disease (CHD) is caused by coronary atherosclerosis and has a high morbidity and mortality rate worldwide. There are challenges in both early screening and treatment of CHD. The appearance and development of CHD is a complex metabolic disorder process. Therefore, to search for new biomarkers of CHD, we analyzed the peripheral blood metabolome in patients with CHD. In the study, a plasma metabolite, 4′-Phosphopantetheine (4-PPanSH), which was discovered by HPLC-MS/MS, as peripheral blood 4-PPanSH decreases, the degree of coronary blockage gradually aggravates. In addition, the 4-PPanSH supplement limited atherosclerotic plaque formation and endothelial injury in mice. Further, in vascular endothelial cells, 4-PPanSH effectively inhibited ROS generation and ox-LDL accumulation. In summary, 4-PPanSH was associated with the degree of coronary stenosis, and the 4-PPanSH supplement reduced atherosclerotic plaque generation, which could be associated with 4-PPanSH acting as a potent antioxidant that inhibits ROS generation and alleviates vascular endothelial injury.
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