电压门控型钠通道中介的单核/巨噬细胞免疫调节在心肌缺血再灌注损伤中的作用
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摘要
研究目的：炎症反应在心肌缺血再灌注(ischemia/reperfusion, I/R)损伤后的组织修复和心室重塑中发挥重要作用。抑制过度的炎症反应能够缩小心梗面积,改善心功能。单核/巨噬细胞是心肌组织损伤修复中驻留时间最长的炎症细胞。单核/巨噬细胞具有异质性：具有促炎症表型的细胞主要执行吞噬、趋化等作用：具有抑制炎症表型的细胞则能促进血管新生、胶原沉积和组织重塑。近年来的研究显示,促进单核/巨噬细胞由促炎症表型向分泌表型转化,将有助于加速组织修复。新近有研究显示,单核/巨噬细胞的电压门控型钠通道(voltage-gated sodium channels, VGSCs/NaV)参与其生物表型的转化。本实验室的前期工作发现VGSCs阻断剂苯妥英钠(phenytoin, PHT)可促进巨噬细胞的旁分泌效应,并加速心肌梗死(myocardial infarction, MI)后组织修复进程,提示VGSCs是调节单核,巨噬细胞生物表型的靶点之一。VGSCs在体内分布广泛,如神经系统、心肌细胞和骨骼肌细胞。脂质体是一种在药剂学和分子生物学研究中常用的药物/基因载体。经静脉注射的脂质体进入血液循环后,能在调理素的介导下被单核/巨噬细胞吞噬,且易在炎症区域富集,利用这一作用可以实现单核/巨噬细胞的靶向性给药。本课题的研究目的是探讨VGSCs阻断剂和激动剂对单核/巨噬细胞表型转化的影响,及脂质体包被的PHT对I/R损伤后组织修复和心室重塑的干预作用。
研究内容与方法：研究内容分为细胞实验和动物实验两部分。细胞实验：以小鼠RAW264.7巨噬细胞系及Wistar大鼠腹腔巨噬细胞为研究对象。利用聚合酶链式反应(polymerase chain reaction, PCR)检测巨噬细胞内VGSCs的表达情况,及将VGSCs阻断剂PHT、河豚毒素(tetrodotoxin, TTX)和激动剂藜芦定(veratridine)作用于不同活化状态的巨噬细胞后表型标志物mRNA水平的表达情况。应用PCR和Western blot方法检测NF-κB信号通路的,mRNA水平及蛋白水平的表达情况。将RNA干扰(RNA interference, RNAi)质粒(pGPU6/Neo-NaV1.9-shRNA)转染进RAW264.7,经G418筛选获得稳定细胞株。对稳定细胞株进行如下检测：PCR鉴定干扰效率；CCK-8法测定增殖活性；流式细胞术检测细胞周期及吞噬能力；trans well小室法检测细胞的迁移功能；PCR检测巨噬细胞标志物的mRNA水平的表达情况。动物实验：以雄性Wistar大鼠为研究对象。薄膜分散法制备PHT脂质体(PHT-lipo),高效液相色谱法(highperformance liquid chromatography, HPLC)测定PHT-lipo在大鼠体内药代动力学。Wistar大鼠随机分为缺血再灌注组(I/R组)和假手术组(Sham组)。每组又分为三个亚组,于手术后即刻、第2、4d经静脉注射给予生理盐水(saline),空白脂质体(Emp-lipo)或PHT-lipo。I/R模型采用左冠状动脉结扎法,缺血45min然后持续再灌注。Sham组为穿线不结扎。于术前、术后1、3、5、7、14、30d抽取大鼠尾静脉血,运用流式细胞术检测大鼠循环中单核细胞CD43+和CD43++两个亚群各时间点的比例。术后第30d采用超声心动图和血流动力学评价心脏功能。随后处死动物,留取心脏标本进行病理染色。Masson染色检测心肌梗死面积、膨展指数、胶原容积分数。麦胚凝集素(wheat germ agglutinin, WGA)检测心肌横断面积。Isolectin B4染色检测毛细血管密度。
结果：细胞实验：1)RAW264.7中有表达的VGSCs α亚基有：NaV1.1、NaV1.3、 NaV1.4、NaV1.5、NaV1.6、NaV1.7、NaV1.9和NaVX。2)应用PHT之后,能使未诱导RAW264.7的M1型标志物CCL5、TNF-α及NOS2表达明显降低,使经脂多糖(lipopolysaccharide, LPS)诱导RAW264.7的M1型标志物IL-1β、CCL2、 CCL5及TNF-α表达降低。TTX能降低未诱导RAW264.7的M1型标志物IL-1p和CCL5表达,降低经LPS诱导RAW264.7的M1型标志物CCL2、CCL5及TNF-α表达。应用藜芦定之后,能使经白介素-4(interleukin-4, IL-4)诱导RAW264.7的M2型标志物Arg1表达降低。3)LPS激活NF-κB信号通路,VGSCs阻断剂能抑制其激活,激动剂则能促进IL-4诱导后的活化。4)成功建立稳定干扰NaV1.9的细胞株,RT-PCR法鉴定干扰效率约80%。下调NaV1.9的表达使RAW264.7的增殖活性、吞噬能力和迁移功能显著降低,M1型标志物CCL5、NOS2表达降低,M2型标志物Arg1、mannose表达升高,NF-κB的表达也降低。5)大鼠腹腔巨噬细胞中有表达的VGSCs是：NaV1.1、NaV1.3、NaV1.4、NaV1.5、NaV1.6、 NaV1.7、NaVX、Scn1b、Scn3b和Scn4b。 PHT抑制LPS引起的M1型巨噬细胞标志物TNF-α、CCL5表达的升高,促进IL-4诱导的M2型巨噬细胞标志物Arg1、TGF-β1的表达。动物实验：1)大鼠尾静脉注射给药后,大鼠体内的PHT和PHT-lipo的血药浓度-时间曲线均符合二室模型。PHT-lipo组的T1/2a(分布半衰期)及T1/2p(清除半衰期)均短于PHT组,AUC略低于PHT组。2)单核细胞亚群在大鼠心肌缺血再灌注模型中存在动态改变：与基线相比,I/R-Saline组CD43+细胞比例从术后第1d开始升高,在第3d达到高峰,之后逐渐下降,在第7d基本恢复基线水平；Sham-Saline组CD43+细胞比例在术后第1d亦明显升高,但在术后第3d已降至基线水平。与Sham-Saline组相比,I/R-Saline组术后第3d CD43+细胞比例显著性升高,其余时间点则无显著性差异。CD43++单核细胞呈现与CD43+细胞相反的变化趋势。3) PHT-lipo能够抑制心肌损伤早期外周血CD43+单核细胞比例的升高,缩小心肌梗死面积,促进梗死区毛细血管增生,降低梗死区胶原沉积和非梗死区代偿性心肌肥大,抑制心室扩张,并改善左心室功能。
结论：阻断细胞内VGSCs活性可以促使巨噬细胞向M2型转化。VGSCs阻断剂通过降低I/R损伤早期CD43+单核细胞比例改善心室重塑和心功能。本研究结果有助于深入阐释VGSCs中介的单核/巨噬细胞免疫调节作用在I/R后组织修复过程中的病理生理学作用,为以单核/巨噬细胞为靶点的I/R损伤后心室重塑干预策略提供了新的实验依据。
Objective:Inflammatory response plays an important role in the healing process and ventricular remodeling after myocardial ischemia/reperfusion (I/R) injury. Inhibition of excessive inflammation could limit the infarct area and ameliorate heart function. Monocytes/macrophages are the major inflammatory cells that stay for longest time in the remodeling process after myocardial injury. Monocytes/macrophages are a heterogeneous population:the inflammatory monocytes/macrophages have a strong capacity of phagocytosis and chemotaxis; the anti-inflammatory monocytes/macrophages could promote angiogeness, collage deposition and tissue repairing. Previous studies shown that switching the inflammatory monocytes/macrophages into the anti-inflammatory monocytes/macrophages maybe benefit for the tissue repair and ventricular remodeling. The functional expression of voltage-gated sodium channels (VGSCs/NaV) was demonstrated in the monocytes/macrophages, which participate the phenotypic polariztion of monocytes/macrophages. Our previous work shown that VGSCs antagonist phenytoin (PHT) could regulate the function of macrophage and accelerate the remodeling process after experimental myocardial infarction (MI). All these results suggest that the VGSCs in monocytes/macrophages would be a regulatory target of phenotypic polarization. The expression of VGSCs was documented in many tissues, such as myocardium, skeletal muscle and nervous system. Liposome is a commonly used vehicle in the field of pharmaceutics and molecular biology. Liposome is phagocyted by the monocytes/macrophages via opsonin after intravenous injection and prone to recruit into the sites of inflammation. This effect would accomplish the goal for monocytes/macrophages targeting. The objective of this project is to exploit the effects of VGSCs antagonist and agonist on monocytes/macrophages phenotype polarization, and investigate the role of PHT-loading liposome (PHT-lipo) in the remodeling process after myocardial I/R injury.
Methods:This research is composed of two parts:cell experiments and animal experiments. Cell experiments:mice macrophage cell line RAW264.7and peritoneal macrophages of male Wistar rat were investigated. The mRNA expression level of VGSCs and phenotypic markers, the protein expression level of NF-κB singnaling in PHT, tetrodotoxin (TTX) and veratridine treated macrophage were quantified by polymerase chain reaction (PCR) or Western blot. RNA interference (RNAi) plasmid (pGPU6/Neo-NaV1.9-shRNA) was transfected into RAW264.7and G418was used to screen the stable cell line. Experiments were performed in NaV1.9knockdown cell line:knockdown efficiency was qualified by PCR; the proliferation was measured by CCK-8; cell cycle and phagocytic ability were analyzed by flow cytometry; migratory ability was detected by transwell chamber migration assay; the mRNA expression level of phenotypic markers was detected by PCR. Animal experiments:PHT-lipo was made by film dispersion method. The estimation of pharmacokinetic characteristics of PHT-lipo was done by high performance liquid chromatography (HPLC). Rats were randomly divided into sham groups and I/R groups. Each group was divided into3subgroups which were intravenous injected with saline, empty liposome (Emp-lipo) or PHT-lipo respectively on0,2,4days after surgery. I/R model was established by left coronary artery ligation, ischemia for45min and sequentially persistent reperfusion. The left coronary artery was not ligated in sham groups. Peripheral blood was extracted from individual rat through the tail vein at base line and1,3,5,7,14,30d after surgery. The proportions of circulating monocyte CD43+and CD43++subsets were analyzed by flow cytometry. At30days after the induction of I/R, the cardiac function was evaluated by echocardiography and invasive left ventricular hemodynamic analysis hemodynamic parameter. Then rats were sacrificed and hearts were harvested for the histology examination. Index of expansion, collagen volume fraction (CVF) and infaret size were analyzed from Masson staining. Cross-sectional area was investigated by wheat germ agglutinin (WGA). The capillary density was calculated by isolectin B4staining.
Results:1) The a subunits of VGSCs expressed in RAW264.7are:NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.9and NaVX.2) The mRNA expression level of CCL5, TNF-a, NOS2(M1markers) in uninduced cell and IL-1β, CCL2, CCL5, TNF-a in LPS induced cell were declined after the treatment of PHT. The mRNA expression level of IL-1β，CCL5in uninduced cell and CCL2, CCL5, TNF-a in LPS induced cell were declined after the treatment of TTX. The mRNA expression level of Argl (M2marker) was decreased in IL-4induced cell after the treatment of veratridine.3) VGSCs antagonist inhibited the activation of NF-κB signaling in LPS-induced RAW264.7; while VGSCs agonist facilitated the activation in IL-4induced cell.4) NaV1.9-deficient stable cell line was established and the expression of NaV1.9was reduced80%. Decreased proliferative, phagocytic and migratory abilities were observed in NaV1.9knockdown RAW264.7cell line. The mRNA expression level of CCL5and NOS2were down-regulated, and Argl and mannose were up-regulated in the stable cell line.5) The expression of VGSCs were confirmed in rat peirtoneal macrophages:NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scnlb, Scn3b and Scn4b. PHT inhibited the enhancement of TNF-a, CCL5in LPS treated cells and promoted the increment of Argl, TGF-β1in IL-4treated cells.2Animal experiments:1) The concentration-time curves of PHT and PHT-lipo fitted two-compartment model in rats. The T1/2a and T1/2β of PHT-lipo were shorter and the AUC was lower than PHT.2) Dynamic changes of monocyte subsets proportions were detected in I/R model. In I/R group, the proportion of CD43+monocyte increased at1d after surgery compared with base line, peaked at3d, and then decreased to the base line at7d. In sham group, the percentage of CD43+monocyte enhanced at1d after surgery compared with base line, declined at3d. The ratio of CD43in I/R group at3d was much higher than sham group at3d. There was no significant difference between the two groups at any other time points. The change of CD43++proportion was contrary to CD43+proportion.3) PHT-lipo significantly decreased circulating CD43+monocytes, which was accompanied by improvement of post-infarction left ventricle (LV) remodeling, as shown by decreased infarct size, enhanced angiogenesis, reduced intersitial fibrosis and cardiomyocyte cross-sectional area, dereased LV expansion index, and improved LV functions.
Conclusions:Block the VGSCs in macrophages could switch the transition of M1into M2polarization in macrophages. PHT-lipo modified the dynamic changes of monocyte subsets and improved the post-infarction healing in rat myocardial I/R model. The present study demonstrates a novel role of VGSCs mediated monocyte/macrophage immunomodulation following myocardial ischemic insult, and provides the experimental basis for monocytes/macophages targeted therapy for the treatment of post-infarction LV remodeling and heart failure.
研究内容与方法：研究内容分为细胞实验和动物实验两部分。细胞实验：以小鼠RAW264.7巨噬细胞系及Wistar大鼠腹腔巨噬细胞为研究对象。利用聚合酶链式反应(polymerase chain reaction, PCR)检测巨噬细胞内VGSCs的表达情况,及将VGSCs阻断剂PHT、河豚毒素(tetrodotoxin, TTX)和激动剂藜芦定(veratridine)作用于不同活化状态的巨噬细胞后表型标志物mRNA水平的表达情况。应用PCR和Western blot方法检测NF-κB信号通路的,mRNA水平及蛋白水平的表达情况。将RNA干扰(RNA interference, RNAi)质粒(pGPU6/Neo-NaV1.9-shRNA)转染进RAW264.7,经G418筛选获得稳定细胞株。对稳定细胞株进行如下检测：PCR鉴定干扰效率；CCK-8法测定增殖活性；流式细胞术检测细胞周期及吞噬能力；trans well小室法检测细胞的迁移功能；PCR检测巨噬细胞标志物的mRNA水平的表达情况。动物实验：以雄性Wistar大鼠为研究对象。薄膜分散法制备PHT脂质体(PHT-lipo),高效液相色谱法(highperformance liquid chromatography, HPLC)测定PHT-lipo在大鼠体内药代动力学。Wistar大鼠随机分为缺血再灌注组(I/R组)和假手术组(Sham组)。每组又分为三个亚组,于手术后即刻、第2、4d经静脉注射给予生理盐水(saline),空白脂质体(Emp-lipo)或PHT-lipo。I/R模型采用左冠状动脉结扎法,缺血45min然后持续再灌注。Sham组为穿线不结扎。于术前、术后1、3、5、7、14、30d抽取大鼠尾静脉血,运用流式细胞术检测大鼠循环中单核细胞CD43+和CD43++两个亚群各时间点的比例。术后第30d采用超声心动图和血流动力学评价心脏功能。随后处死动物,留取心脏标本进行病理染色。Masson染色检测心肌梗死面积、膨展指数、胶原容积分数。麦胚凝集素(wheat germ agglutinin, WGA)检测心肌横断面积。Isolectin B4染色检测毛细血管密度。
结果：细胞实验：1)RAW264.7中有表达的VGSCs α亚基有：NaV1.1、NaV1.3、 NaV1.4、NaV1.5、NaV1.6、NaV1.7、NaV1.9和NaVX。2)应用PHT之后,能使未诱导RAW264.7的M1型标志物CCL5、TNF-α及NOS2表达明显降低,使经脂多糖(lipopolysaccharide, LPS)诱导RAW264.7的M1型标志物IL-1β、CCL2、 CCL5及TNF-α表达降低。TTX能降低未诱导RAW264.7的M1型标志物IL-1p和CCL5表达,降低经LPS诱导RAW264.7的M1型标志物CCL2、CCL5及TNF-α表达。应用藜芦定之后,能使经白介素-4(interleukin-4, IL-4)诱导RAW264.7的M2型标志物Arg1表达降低。3)LPS激活NF-κB信号通路,VGSCs阻断剂能抑制其激活,激动剂则能促进IL-4诱导后的活化。4)成功建立稳定干扰NaV1.9的细胞株,RT-PCR法鉴定干扰效率约80%。下调NaV1.9的表达使RAW264.7的增殖活性、吞噬能力和迁移功能显著降低,M1型标志物CCL5、NOS2表达降低,M2型标志物Arg1、mannose表达升高,NF-κB的表达也降低。5)大鼠腹腔巨噬细胞中有表达的VGSCs是：NaV1.1、NaV1.3、NaV1.4、NaV1.5、NaV1.6、 NaV1.7、NaVX、Scn1b、Scn3b和Scn4b。 PHT抑制LPS引起的M1型巨噬细胞标志物TNF-α、CCL5表达的升高,促进IL-4诱导的M2型巨噬细胞标志物Arg1、TGF-β1的表达。动物实验：1)大鼠尾静脉注射给药后,大鼠体内的PHT和PHT-lipo的血药浓度-时间曲线均符合二室模型。PHT-lipo组的T1/2a(分布半衰期)及T1/2p(清除半衰期)均短于PHT组,AUC略低于PHT组。2)单核细胞亚群在大鼠心肌缺血再灌注模型中存在动态改变：与基线相比,I/R-Saline组CD43+细胞比例从术后第1d开始升高,在第3d达到高峰,之后逐渐下降,在第7d基本恢复基线水平；Sham-Saline组CD43+细胞比例在术后第1d亦明显升高,但在术后第3d已降至基线水平。与Sham-Saline组相比,I/R-Saline组术后第3d CD43+细胞比例显著性升高,其余时间点则无显著性差异。CD43++单核细胞呈现与CD43+细胞相反的变化趋势。3) PHT-lipo能够抑制心肌损伤早期外周血CD43+单核细胞比例的升高,缩小心肌梗死面积,促进梗死区毛细血管增生,降低梗死区胶原沉积和非梗死区代偿性心肌肥大,抑制心室扩张,并改善左心室功能。
结论：阻断细胞内VGSCs活性可以促使巨噬细胞向M2型转化。VGSCs阻断剂通过降低I/R损伤早期CD43+单核细胞比例改善心室重塑和心功能。本研究结果有助于深入阐释VGSCs中介的单核/巨噬细胞免疫调节作用在I/R后组织修复过程中的病理生理学作用,为以单核/巨噬细胞为靶点的I/R损伤后心室重塑干预策略提供了新的实验依据。
Objective:Inflammatory response plays an important role in the healing process and ventricular remodeling after myocardial ischemia/reperfusion (I/R) injury. Inhibition of excessive inflammation could limit the infarct area and ameliorate heart function. Monocytes/macrophages are the major inflammatory cells that stay for longest time in the remodeling process after myocardial injury. Monocytes/macrophages are a heterogeneous population:the inflammatory monocytes/macrophages have a strong capacity of phagocytosis and chemotaxis; the anti-inflammatory monocytes/macrophages could promote angiogeness, collage deposition and tissue repairing. Previous studies shown that switching the inflammatory monocytes/macrophages into the anti-inflammatory monocytes/macrophages maybe benefit for the tissue repair and ventricular remodeling. The functional expression of voltage-gated sodium channels (VGSCs/NaV) was demonstrated in the monocytes/macrophages, which participate the phenotypic polariztion of monocytes/macrophages. Our previous work shown that VGSCs antagonist phenytoin (PHT) could regulate the function of macrophage and accelerate the remodeling process after experimental myocardial infarction (MI). All these results suggest that the VGSCs in monocytes/macrophages would be a regulatory target of phenotypic polarization. The expression of VGSCs was documented in many tissues, such as myocardium, skeletal muscle and nervous system. Liposome is a commonly used vehicle in the field of pharmaceutics and molecular biology. Liposome is phagocyted by the monocytes/macrophages via opsonin after intravenous injection and prone to recruit into the sites of inflammation. This effect would accomplish the goal for monocytes/macrophages targeting. The objective of this project is to exploit the effects of VGSCs antagonist and agonist on monocytes/macrophages phenotype polarization, and investigate the role of PHT-loading liposome (PHT-lipo) in the remodeling process after myocardial I/R injury.
Methods:This research is composed of two parts:cell experiments and animal experiments. Cell experiments:mice macrophage cell line RAW264.7and peritoneal macrophages of male Wistar rat were investigated. The mRNA expression level of VGSCs and phenotypic markers, the protein expression level of NF-κB singnaling in PHT, tetrodotoxin (TTX) and veratridine treated macrophage were quantified by polymerase chain reaction (PCR) or Western blot. RNA interference (RNAi) plasmid (pGPU6/Neo-NaV1.9-shRNA) was transfected into RAW264.7and G418was used to screen the stable cell line. Experiments were performed in NaV1.9knockdown cell line:knockdown efficiency was qualified by PCR; the proliferation was measured by CCK-8; cell cycle and phagocytic ability were analyzed by flow cytometry; migratory ability was detected by transwell chamber migration assay; the mRNA expression level of phenotypic markers was detected by PCR. Animal experiments:PHT-lipo was made by film dispersion method. The estimation of pharmacokinetic characteristics of PHT-lipo was done by high performance liquid chromatography (HPLC). Rats were randomly divided into sham groups and I/R groups. Each group was divided into3subgroups which were intravenous injected with saline, empty liposome (Emp-lipo) or PHT-lipo respectively on0,2,4days after surgery. I/R model was established by left coronary artery ligation, ischemia for45min and sequentially persistent reperfusion. The left coronary artery was not ligated in sham groups. Peripheral blood was extracted from individual rat through the tail vein at base line and1,3,5,7,14,30d after surgery. The proportions of circulating monocyte CD43+and CD43++subsets were analyzed by flow cytometry. At30days after the induction of I/R, the cardiac function was evaluated by echocardiography and invasive left ventricular hemodynamic analysis hemodynamic parameter. Then rats were sacrificed and hearts were harvested for the histology examination. Index of expansion, collagen volume fraction (CVF) and infaret size were analyzed from Masson staining. Cross-sectional area was investigated by wheat germ agglutinin (WGA). The capillary density was calculated by isolectin B4staining.
Results:1) The a subunits of VGSCs expressed in RAW264.7are:NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.9and NaVX.2) The mRNA expression level of CCL5, TNF-a, NOS2(M1markers) in uninduced cell and IL-1β, CCL2, CCL5, TNF-a in LPS induced cell were declined after the treatment of PHT. The mRNA expression level of IL-1β，CCL5in uninduced cell and CCL2, CCL5, TNF-a in LPS induced cell were declined after the treatment of TTX. The mRNA expression level of Argl (M2marker) was decreased in IL-4induced cell after the treatment of veratridine.3) VGSCs antagonist inhibited the activation of NF-κB signaling in LPS-induced RAW264.7; while VGSCs agonist facilitated the activation in IL-4induced cell.4) NaV1.9-deficient stable cell line was established and the expression of NaV1.9was reduced80%. Decreased proliferative, phagocytic and migratory abilities were observed in NaV1.9knockdown RAW264.7cell line. The mRNA expression level of CCL5and NOS2were down-regulated, and Argl and mannose were up-regulated in the stable cell line.5) The expression of VGSCs were confirmed in rat peirtoneal macrophages:NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scnlb, Scn3b and Scn4b. PHT inhibited the enhancement of TNF-a, CCL5in LPS treated cells and promoted the increment of Argl, TGF-β1in IL-4treated cells.2Animal experiments:1) The concentration-time curves of PHT and PHT-lipo fitted two-compartment model in rats. The T1/2a and T1/2β of PHT-lipo were shorter and the AUC was lower than PHT.2) Dynamic changes of monocyte subsets proportions were detected in I/R model. In I/R group, the proportion of CD43+monocyte increased at1d after surgery compared with base line, peaked at3d, and then decreased to the base line at7d. In sham group, the percentage of CD43+monocyte enhanced at1d after surgery compared with base line, declined at3d. The ratio of CD43in I/R group at3d was much higher than sham group at3d. There was no significant difference between the two groups at any other time points. The change of CD43++proportion was contrary to CD43+proportion.3) PHT-lipo significantly decreased circulating CD43+monocytes, which was accompanied by improvement of post-infarction left ventricle (LV) remodeling, as shown by decreased infarct size, enhanced angiogenesis, reduced intersitial fibrosis and cardiomyocyte cross-sectional area, dereased LV expansion index, and improved LV functions.
Conclusions:Block the VGSCs in macrophages could switch the transition of M1into M2polarization in macrophages. PHT-lipo modified the dynamic changes of monocyte subsets and improved the post-infarction healing in rat myocardial I/R model. The present study demonstrates a novel role of VGSCs mediated monocyte/macrophage immunomodulation following myocardial ischemic insult, and provides the experimental basis for monocytes/macophages targeted therapy for the treatment of post-infarction LV remodeling and heart failure.
引文
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