溶血磷脂酸对心梗过程中的免疫炎症反应及连接蛋白43的调控
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摘要
急性心肌梗塞(AMI)是严重影响人类健康与生命的疾病,心梗并发心律失常是心肌梗塞死亡的重要原因。溶血磷脂酸(LPA)是细胞膜磷脂代谢的一种中间产物,心梗时局部心肌和血浆中的LPA浓度增高,并可引起心律失常。在心梗过程中,心肌梗塞的梗塞区和非梗塞区均有血管周围炎和大量炎性细胞浸润,外周血中伴有各种炎性因子的增多,提示心肌梗塞是一个非感染性的免疫炎症过程,免疫炎症反应在心梗中发挥了重要的作用。目前许多研究都集中在LPA对缺血心肌细胞的作用机制方面,而LPA的免疫调控作用对心肌细胞之间的信号通道——缝隙连接通道蛋白43(Cx43)的表达,及其诱发心律失常的研究尚无报道。本实验采用多种实验方法,从免疫炎症入手,在整体、器官、细胞分子水平上系统观察了在心梗时LPA对淋巴细胞,TNF-α,Cx43变化的影响及其与心律失常的关系。结论如下:
①在心梗模型大鼠中,LPA的致心律失常作用与机体的免疫状态有关,免疫系统被抑制的大鼠,心律失常发生率降低,而免疫系统增强大鼠心律失常发生率明显增多;
②LPA可诱发培养的淋巴细胞合成并释放TNF-α;
③LPA可使淋巴细胞电压依赖性钾通道[K(v)]、钙激活性钾通道[K(Ca)]通道电流增大,促进K+内流;
④LPA可使心室肌Cx43的表达下降,这一作用与机体的免疫状态有关,免疫系统增强大鼠心肌Cx43的表达下降更为明显。
因此,这一研究首次证明了LPA可通过激活淋巴细胞,释放TNF-α,使Cx43降解而引起心律失常,并证明了心梗过程中,免疫炎症反应对心律失常的发生、发展产生重要的影响。
Lysophosphatidic acid is a intermediary metabolite of phospholipid in cell membrane, it also releases from activated platelets. Through the clinic epidemiology investigation about incidence of arrhythmia in ovary cancer, We observed that the incidence rate of arrhythmia of ovary cancer and hepatoma were 32.38% and 10.19% respectively. This result suggests that LPA may involve in arrhythmia occurance.
Lysophosphatidic acid has a wide spectrum of biological effects on variety cells via G-protein-coupled cell surface receptors. More studies focused on the role of LPA in physiological and pathological processes. During the course of acute myocardial infarction, the number of white blood cell increased, inflammatory cell infiltration were surrounding the coronary blood vessels, and various of cytokines was significantly increased. This suggests that AMI is a process of immune inflammatory response, inflammatory cell and various of cytokines played an important role of the induction of arrhythmia.
Connexin 43 is the gap junction channels of the ventricular myocytes.If connexin 43 was reduced by 50%, the interior of the heart conduction slowed down, leading to arrhythmia.
We use the immune-enhancing and immunosuppressive drugs (thymopeptide and cyclophosphamide) to interfere with the immune system of laboratory animals for 8 days, leukocyte in peripheral blood will be accoutted to confirm the immune enhancement or immune suppression . Ligating lower left branch of the left coronary artery of rats , then injecting intravenous lysophosphatidic acid into the heart surface, and recording the lantency of arrhythmia incidence. We found ,in immune-enhancing group of animals with lysophosphatidic acid injection, the arrhythmia occurred earlier than the normal control group, the incidence rate of arrhythmia significantly increased, on the other hand, immune suppression group with injection of lysophosphatidic acid, arrhythmia occurred later than the normal control group, the incidence rate of arrhythmia also decreased significantly. It proved that the effect of Lysophosphatidic acid on arrhythmia is highly related with the immune system situation. when the body's immune system was suppressed, the incidence rate of arrhythmia will decrease.
We cultured human T lymphocytes (Jurkat T), add in the culture medium lysophosphatidic acid, collecting of culture medium timingly, then using double-sandwich ELISA method to analyze the tumor necrosis factor (TNF) concentration in the culture medium. the results proved that lysophosphatidic acid can activate Jurkat T lymphocytes, induce TNF-αgene expression, then promote of TNF-αsynthesis and release.
The voltage dependent potassium channels [K (v)]and calcium-activated potassium channels [K (Ca)] characteristics of the Jurkat T cells are studied by Patch-clamp technique. Studies have shown that lysophosphatidic acid can increases K (v) channel current of Jurkat T cells, promoting of K + influx, K (Ca) channel conductance increased, that means the number of channels increased, further evidence of lysophosphatidic acid-activated Jurkat T lymphocytes, inducing by TNF-αgene expression, the promoting of TNF-αsynthesis and release is the role of Jurkat T lymphocytes by activating membrane K (v) channels and K (Ca) channel to the implementation.
Of our in vivo animal model of acute myocardial infarction (including blank control group, normal control group, immune-enhancing group and immune suppression group) of the heart, by immunohistochemical staining method was used to observe the expression of Cx43 and found that: myocardial infarction after injection of exogenous LPA of the animals, Cx43 expression in ventricular myocytes than normal animals decreased immunoenhancement animals decreased the expression of Cx43 is more obvious, and the immune suppression of animals the expression of Cx43 is similar to normal animals, LPA specific blocker may be partially blocked LPA so that the decline in the role of Cx43 expression. It prove that LPA caused the degradation of Cx43 and decreased expression, which may be arrhythmogenic LPA an important way.
The above results suggest that: LPA involved in acute myocardial infarction after the occurrence of arrhythmia, the mechanism of immune regulation are the releasing of cytokines and implementation by inflammatory cells, our experiments prove that LPA can activate T lymphocytes, release of cytokines TNF, then inhibit the expression of Cx43 ,and all of above can increase the occurrence of arrhythmia.
①在心梗模型大鼠中,LPA的致心律失常作用与机体的免疫状态有关,免疫系统被抑制的大鼠,心律失常发生率降低,而免疫系统增强大鼠心律失常发生率明显增多;
②LPA可诱发培养的淋巴细胞合成并释放TNF-α;
③LPA可使淋巴细胞电压依赖性钾通道[K(v)]、钙激活性钾通道[K(Ca)]通道电流增大,促进K+内流;
④LPA可使心室肌Cx43的表达下降,这一作用与机体的免疫状态有关,免疫系统增强大鼠心肌Cx43的表达下降更为明显。
因此,这一研究首次证明了LPA可通过激活淋巴细胞,释放TNF-α,使Cx43降解而引起心律失常,并证明了心梗过程中,免疫炎症反应对心律失常的发生、发展产生重要的影响。
Lysophosphatidic acid is a intermediary metabolite of phospholipid in cell membrane, it also releases from activated platelets. Through the clinic epidemiology investigation about incidence of arrhythmia in ovary cancer, We observed that the incidence rate of arrhythmia of ovary cancer and hepatoma were 32.38% and 10.19% respectively. This result suggests that LPA may involve in arrhythmia occurance.
Lysophosphatidic acid has a wide spectrum of biological effects on variety cells via G-protein-coupled cell surface receptors. More studies focused on the role of LPA in physiological and pathological processes. During the course of acute myocardial infarction, the number of white blood cell increased, inflammatory cell infiltration were surrounding the coronary blood vessels, and various of cytokines was significantly increased. This suggests that AMI is a process of immune inflammatory response, inflammatory cell and various of cytokines played an important role of the induction of arrhythmia.
Connexin 43 is the gap junction channels of the ventricular myocytes.If connexin 43 was reduced by 50%, the interior of the heart conduction slowed down, leading to arrhythmia.
We use the immune-enhancing and immunosuppressive drugs (thymopeptide and cyclophosphamide) to interfere with the immune system of laboratory animals for 8 days, leukocyte in peripheral blood will be accoutted to confirm the immune enhancement or immune suppression . Ligating lower left branch of the left coronary artery of rats , then injecting intravenous lysophosphatidic acid into the heart surface, and recording the lantency of arrhythmia incidence. We found ,in immune-enhancing group of animals with lysophosphatidic acid injection, the arrhythmia occurred earlier than the normal control group, the incidence rate of arrhythmia significantly increased, on the other hand, immune suppression group with injection of lysophosphatidic acid, arrhythmia occurred later than the normal control group, the incidence rate of arrhythmia also decreased significantly. It proved that the effect of Lysophosphatidic acid on arrhythmia is highly related with the immune system situation. when the body's immune system was suppressed, the incidence rate of arrhythmia will decrease.
We cultured human T lymphocytes (Jurkat T), add in the culture medium lysophosphatidic acid, collecting of culture medium timingly, then using double-sandwich ELISA method to analyze the tumor necrosis factor (TNF) concentration in the culture medium. the results proved that lysophosphatidic acid can activate Jurkat T lymphocytes, induce TNF-αgene expression, then promote of TNF-αsynthesis and release.
The voltage dependent potassium channels [K (v)]and calcium-activated potassium channels [K (Ca)] characteristics of the Jurkat T cells are studied by Patch-clamp technique. Studies have shown that lysophosphatidic acid can increases K (v) channel current of Jurkat T cells, promoting of K + influx, K (Ca) channel conductance increased, that means the number of channels increased, further evidence of lysophosphatidic acid-activated Jurkat T lymphocytes, inducing by TNF-αgene expression, the promoting of TNF-αsynthesis and release is the role of Jurkat T lymphocytes by activating membrane K (v) channels and K (Ca) channel to the implementation.
Of our in vivo animal model of acute myocardial infarction (including blank control group, normal control group, immune-enhancing group and immune suppression group) of the heart, by immunohistochemical staining method was used to observe the expression of Cx43 and found that: myocardial infarction after injection of exogenous LPA of the animals, Cx43 expression in ventricular myocytes than normal animals decreased immunoenhancement animals decreased the expression of Cx43 is more obvious, and the immune suppression of animals the expression of Cx43 is similar to normal animals, LPA specific blocker may be partially blocked LPA so that the decline in the role of Cx43 expression. It prove that LPA caused the degradation of Cx43 and decreased expression, which may be arrhythmogenic LPA an important way.
The above results suggest that: LPA involved in acute myocardial infarction after the occurrence of arrhythmia, the mechanism of immune regulation are the releasing of cytokines and implementation by inflammatory cells, our experiments prove that LPA can activate T lymphocytes, release of cytokines TNF, then inhibit the expression of Cx43 ,and all of above can increase the occurrence of arrhythmia.
引文
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