急性冠状动脉综合征患者CD4~+、CD4~+CD28~(null)T细胞钾通道的表达及意义
|
摘要
第一部分急性冠状动脉综合征患者CD4~+、CD4~+CD28~(null)T细胞Kv1．3钾通道的表达及意义
【目的】研究急性冠状动脉综合征(acute coronary syndrome，ACS)患者外周血中CD4~+T细胞及其亚型CD4~+CD28~(null)T细胞活化前后Kv1．3钾通道数目的变化以及Kv1．3钾通道阻滞剂对CD4~+T细胞活化表达的影响，探讨Kv1．3钾通道在动脉粥样斑块中的意义。
【方法】用免疫磁珠法分离出27例ACS患者外周血中的CD4~+T细胞，其中12例进一步分出亚型CD4~+CD28~(null)和CD4~+CD28~+T细胞，采用全细胞膜片钳技术记录细胞活化前及经CD3抗体活化72h后的Kv1．3钾电流。CD4~+T细胞活化时分别加入终浓度为0．1、1、10nmol／L特异性Kv1．3钾通道阻滞剂重组玛格斑蝎毒素(recombinant margatoxin，rMgTX)，共同培养72h。用逆转录-聚合酶链反应(reverse transcription-polymerase chain reaction，RT-PCR)法检测CD4~+T细胞的干扰素-γ、肿瘤坏死因子-α(tumor necrosis factor，TNF-α)及颗粒酶B mRNA的表达。
【结果】活化后CD4~+、CD4~+CD28~(null)T细胞的Kv1．3钾通道的峰电流均明显增加，细胞平均通道数分别增加约90％、60％(活化前后每个细胞的通道数分别为402±88比752±275、553±328比874±400；各P＜0．05)，具有统计学意义。活化前CD4~+CD28~(null)T细胞Kv1．3钾通道的平均数目比CD4~+CD28~+T细胞多约40％(P＜0．05)，活化后两者无明显差别(P=0．102)。不同浓度的rMgTX均下调CD4~+T细胞活化后干扰素-γ、TNF-α、颗粒酶B mRNA的表达，各浓度组间的干扰素-γ、TNF-α、颗粒酶B mRNA的表达均有差别，具有统计学意义(各P＜0．01)，rMgTX的浓度越高，各mRNA的表达越低。
【结论】ACS患者外周血CD4~+T细胞及其亚型CD4~+CD28~(null)T细胞活化后Kv1．3钾通道表达增加，特异性Kv1．3通道阻滞剂rMgTX呈浓度依赖性地抑制CD4~+T细胞活化时干扰素-γ、TNF-α及颗粒酶B mRNA的表达，提示CD4~+T细胞特别是CD4~+CD28~(null)T细胞的Kv1．3钾通道可能作为预防动脉粥样斑块不稳定的潜在治疗靶点。
第二部分急性冠状动脉综合征患者CD4~+、CD4~+CD28~(null)T细胞IKCa1钾通道的表达及意义
【目的】研究ACS患者外周血中CD4~+T细胞及CD4~+CD28~(null)亚型活化前后IKCa1钾通道数目的变化以及IKCa1钾通道阻滞剂对活化的CD4~+T细胞表达效应分子的影响，探讨IKCa1钾通道对动脉粥样斑块的意义。
【方法】用免疫磁珠法分离出24例ACS患者外周血中的CD4~+T细胞，其中12例进一步分出亚型CD4~+CD28~(null)T细胞，采用全细胞膜片钳技术记录细胞活化前及活化3d后的IKCa1钾电流。CD4~+T细胞活化3d后分别加入终浓度为0．2、1、5μmol／L特异性IKCa1钾通道阻滞剂TRAM-34，再继续活化3d。用RT-PCR法检测CD4~+T细胞的干扰素-γ、TNF-α及颗粒酶B mRNA的表达。
【结果】活化后，CD4~+、CD4~+CD28~(null) T细胞的IKCa1通道数目分别增加了9倍和8倍(活化前、后2种T细胞的通道数分别为45±18比439±161，56±16比497±174；各P＜0．01)，2种T细胞的通道密度均增加了近3倍(各P＜0．01)。活化前、后CD4~+CD28~(null)和CD4~+CD28~+T细胞之间的通道数目及通道密度均无差别。不同浓度的TRAM-34均下调CD4~+T细胞活化后干扰素-γ、TNF-α及颗粒酶B mRNA的表达，各浓度组间干扰素-γ、TNF-α及颗粒酶B mRNA的表达均有差异，具有统计学意义(各P＜0．01)，TRAM-34的浓度越高，各mRNA的表达越低。
【结论】ACS患者外周血CD4~+CD4~+CD28~(null)T细胞活化后IKCa1的通道数目及通道密度均明显增加，特异性IKCa1通道阻滞剂TRAM-34呈浓度依赖性地抑制活化的CD4~+T细胞表达干扰素-γ、TNF-α及颗粒酶B，提示活化的CD4~+T细胞的IKCa1钾通道可能在动脉粥样硬化中起着重要作用，IKCa1钾通道阻滞剂可能用于治疗动脉粥样硬化。
Part 1 Kv1.3 Potassium Channel Expression on CD4~+ and CD4~+CD28~(null)T Cells in Patients with Acute Coronary Syndrome and ItsImplications
【Objective】To study the changes of Kv1.3 channel expression during activation onCD4~+ and CD4~+CD28~(null) T cells in peripheral blood of acute coronary syndrome(ACS)patients and the effects of Kv1.3-specific channel blocker on effectors expression ofCD4~+ T cell after activation, further discuss the implications of Kv1.3 channel foratheromatous plaques development.
【Methods】CD4~+ T cells in all of and subsets CD4~+CD28~(null)/CD4~+CD28~+ T cells in12 of 27 ACS patients were isolated from peripheral blood with magnetic cell sorting.The Kv1.3 currents for three types of T cells above were recorded with whole-cellpatch-clamp technique before and 72 hours after activation by purified anti-humanCD3 mAb.Upon activation, 0.1, 1, 10nmol/L of recombinant Margatoxin (rMgTX), a specific blocker of Kv1.3 channel, were added separately to CD4~+ T cells.72 hourslater, the mRNA expressions of interferon gamma, tumor necrosis factor alpha(TNF-α), granzyme B in CD4~+ T cells were determined by reverse transcription-PCR.
【Results】After activation all peak currents of Kv1.3 channel on CD4~+、CD4~+CD28~(null) T cells were significantly enlarged, and the mean Kv1.3 channelnumbers per cell of each kind of cell aforementioned were respectively increased byaround 90%, 60% (402±88 vs.752±275, 553±328 vs.874±400 channels per cellbefore vs.after activation respectively, both P<0.05).The channels on each restingCD4~+CD28~(null) T cells were about 40% more than those on each resting CD4~+CD28~+ Tcells(P<0.05), whereas there was no difference in channels between the bothactivated T cells(P=0.102).The mRNA expression of interferon gamma, TNF-αand granzyme B were down-regulated by all of rMgTX, and differential expressionof each mRNA existed among varied concentration of rMgTX (P<0.01, respectively).The larger dose of rMgTX, the smaller expression of each mRNA.
【Conclusions】kv1.3 channels increased largely on peripheral blood CD4~+T cellsand its subset CD4~+CD28~(null) T cells after activation in ACS patients, and Kv1.3-specific channel blocker rMgTX inhibited the mRNA expression of interferongamma, TNF-αand granzyme B in CD4~+ T cells in a dose-depend mode.Kv1.3channel on CD4~+ T cells especially on CD4~+CD28~(null) T cells, thus, may be suggestedas a potential therapeutic target for preventing atheromatous plaques fromdestablization.
Part 2 IKCa1 Potassium Channel Expression on CD4~+ andCD4~+CD28~(null) T Cells in Patients with Acute Coronary Syndrome andIts Implications
【Objective】To study the number changes of IKCa1 channel during activation onperipheral blood CD4~+ T cells and its subset CD4~+CD28~(null) in ACS patients and theeffects of IKCa1-specific channel blocker on effectors expression of activated CD4~+T cell, further discuss the implications of IKCa1 channel for atheromatous plaques.
【Methods】CD4+ T cells in all of and CD4~+CD28~(null) T cells in 12 of 24 ACSpatients were isolated from peripheral blood through magnetic cell sorting.Thewhole-cell IKCa1 currents of T cells above were recorded with patch-clamptechnique before and 3 days after activation by purified anti-human CD3 mAb.0.2, 1,5μmol/L of TRAM-34, a specific blocker of IKCa1 channel, were added separatelyto 3-day pre-activated CD4~+T cells, and 3 days' activation followed.The mRNAexpressions of interferon gamma, TNF-α, granzyme B in CD4~+ T cells were detectedby reverse transcription-PCR.
【Results】IKCa1 channels on each activated CD4~+ and CD4~+CD28~(null) T cell wererespectively proximately 9 and 8 times higher than those on each resting CD4~+ andCD4~+CD28~(null) T cell (439±161 vs.45±18, 497±174 vs.56±16 channels per cell aftervs.before activation respectively, both P<0.05).Both activated T cells had up totriple channel density, compared to their resting ones (both P<0.05).The numbersand density of IKCa1 channel were parallel between both T cells regardless ofactivation.The mRNA expression of interferon gamma, TNF-α, and granzyme Bwere down-regulated by all dose of TRAM-34, and differential expression of eachmRNA existed among varied dose of TRAM-34(P<0.01, respectively).The largerdose of rMgTX, the smaller expression of each mRNA.
【Conclusions】IKCa1 channel numbers and density increased significantly on peripheral blood CD4~+ and CD4~+CD28~(null) T cells after activation in ACS patients,and IKCa1-specific channel blocker TRAM-34 inhibited the mRNA expressions ofinterferon gamma, TNF-α, and granzyme B in activated CD4~+ T cells in adose-depend pattern.It may be indicated that IKCa1 channel on activated CD4~+ Tcells play an important role in atherosclerosis, and that IKCa1 channel blockers haveuse in therapeutic manipulation of atherosclerosis.
【目的】研究急性冠状动脉综合征(acute coronary syndrome，ACS)患者外周血中CD4~+T细胞及其亚型CD4~+CD28~(null)T细胞活化前后Kv1．3钾通道数目的变化以及Kv1．3钾通道阻滞剂对CD4~+T细胞活化表达的影响，探讨Kv1．3钾通道在动脉粥样斑块中的意义。
【方法】用免疫磁珠法分离出27例ACS患者外周血中的CD4~+T细胞，其中12例进一步分出亚型CD4~+CD28~(null)和CD4~+CD28~+T细胞，采用全细胞膜片钳技术记录细胞活化前及经CD3抗体活化72h后的Kv1．3钾电流。CD4~+T细胞活化时分别加入终浓度为0．1、1、10nmol／L特异性Kv1．3钾通道阻滞剂重组玛格斑蝎毒素(recombinant margatoxin，rMgTX)，共同培养72h。用逆转录-聚合酶链反应(reverse transcription-polymerase chain reaction，RT-PCR)法检测CD4~+T细胞的干扰素-γ、肿瘤坏死因子-α(tumor necrosis factor，TNF-α)及颗粒酶B mRNA的表达。
【结果】活化后CD4~+、CD4~+CD28~(null)T细胞的Kv1．3钾通道的峰电流均明显增加，细胞平均通道数分别增加约90％、60％(活化前后每个细胞的通道数分别为402±88比752±275、553±328比874±400；各P＜0．05)，具有统计学意义。活化前CD4~+CD28~(null)T细胞Kv1．3钾通道的平均数目比CD4~+CD28~+T细胞多约40％(P＜0．05)，活化后两者无明显差别(P=0．102)。不同浓度的rMgTX均下调CD4~+T细胞活化后干扰素-γ、TNF-α、颗粒酶B mRNA的表达，各浓度组间的干扰素-γ、TNF-α、颗粒酶B mRNA的表达均有差别，具有统计学意义(各P＜0．01)，rMgTX的浓度越高，各mRNA的表达越低。
【结论】ACS患者外周血CD4~+T细胞及其亚型CD4~+CD28~(null)T细胞活化后Kv1．3钾通道表达增加，特异性Kv1．3通道阻滞剂rMgTX呈浓度依赖性地抑制CD4~+T细胞活化时干扰素-γ、TNF-α及颗粒酶B mRNA的表达，提示CD4~+T细胞特别是CD4~+CD28~(null)T细胞的Kv1．3钾通道可能作为预防动脉粥样斑块不稳定的潜在治疗靶点。
第二部分急性冠状动脉综合征患者CD4~+、CD4~+CD28~(null)T细胞IKCa1钾通道的表达及意义
【目的】研究ACS患者外周血中CD4~+T细胞及CD4~+CD28~(null)亚型活化前后IKCa1钾通道数目的变化以及IKCa1钾通道阻滞剂对活化的CD4~+T细胞表达效应分子的影响，探讨IKCa1钾通道对动脉粥样斑块的意义。
【方法】用免疫磁珠法分离出24例ACS患者外周血中的CD4~+T细胞，其中12例进一步分出亚型CD4~+CD28~(null)T细胞，采用全细胞膜片钳技术记录细胞活化前及活化3d后的IKCa1钾电流。CD4~+T细胞活化3d后分别加入终浓度为0．2、1、5μmol／L特异性IKCa1钾通道阻滞剂TRAM-34，再继续活化3d。用RT-PCR法检测CD4~+T细胞的干扰素-γ、TNF-α及颗粒酶B mRNA的表达。
【结果】活化后，CD4~+、CD4~+CD28~(null) T细胞的IKCa1通道数目分别增加了9倍和8倍(活化前、后2种T细胞的通道数分别为45±18比439±161，56±16比497±174；各P＜0．01)，2种T细胞的通道密度均增加了近3倍(各P＜0．01)。活化前、后CD4~+CD28~(null)和CD4~+CD28~+T细胞之间的通道数目及通道密度均无差别。不同浓度的TRAM-34均下调CD4~+T细胞活化后干扰素-γ、TNF-α及颗粒酶B mRNA的表达，各浓度组间干扰素-γ、TNF-α及颗粒酶B mRNA的表达均有差异，具有统计学意义(各P＜0．01)，TRAM-34的浓度越高，各mRNA的表达越低。
【结论】ACS患者外周血CD4~+CD4~+CD28~(null)T细胞活化后IKCa1的通道数目及通道密度均明显增加，特异性IKCa1通道阻滞剂TRAM-34呈浓度依赖性地抑制活化的CD4~+T细胞表达干扰素-γ、TNF-α及颗粒酶B，提示活化的CD4~+T细胞的IKCa1钾通道可能在动脉粥样硬化中起着重要作用，IKCa1钾通道阻滞剂可能用于治疗动脉粥样硬化。
Part 1 Kv1.3 Potassium Channel Expression on CD4~+ and CD4~+CD28~(null)T Cells in Patients with Acute Coronary Syndrome and ItsImplications
【Objective】To study the changes of Kv1.3 channel expression during activation onCD4~+ and CD4~+CD28~(null) T cells in peripheral blood of acute coronary syndrome(ACS)patients and the effects of Kv1.3-specific channel blocker on effectors expression ofCD4~+ T cell after activation, further discuss the implications of Kv1.3 channel foratheromatous plaques development.
【Methods】CD4~+ T cells in all of and subsets CD4~+CD28~(null)/CD4~+CD28~+ T cells in12 of 27 ACS patients were isolated from peripheral blood with magnetic cell sorting.The Kv1.3 currents for three types of T cells above were recorded with whole-cellpatch-clamp technique before and 72 hours after activation by purified anti-humanCD3 mAb.Upon activation, 0.1, 1, 10nmol/L of recombinant Margatoxin (rMgTX), a specific blocker of Kv1.3 channel, were added separately to CD4~+ T cells.72 hourslater, the mRNA expressions of interferon gamma, tumor necrosis factor alpha(TNF-α), granzyme B in CD4~+ T cells were determined by reverse transcription-PCR.
【Results】After activation all peak currents of Kv1.3 channel on CD4~+、CD4~+CD28~(null) T cells were significantly enlarged, and the mean Kv1.3 channelnumbers per cell of each kind of cell aforementioned were respectively increased byaround 90%, 60% (402±88 vs.752±275, 553±328 vs.874±400 channels per cellbefore vs.after activation respectively, both P<0.05).The channels on each restingCD4~+CD28~(null) T cells were about 40% more than those on each resting CD4~+CD28~+ Tcells(P<0.05), whereas there was no difference in channels between the bothactivated T cells(P=0.102).The mRNA expression of interferon gamma, TNF-αand granzyme B were down-regulated by all of rMgTX, and differential expressionof each mRNA existed among varied concentration of rMgTX (P<0.01, respectively).The larger dose of rMgTX, the smaller expression of each mRNA.
【Conclusions】kv1.3 channels increased largely on peripheral blood CD4~+T cellsand its subset CD4~+CD28~(null) T cells after activation in ACS patients, and Kv1.3-specific channel blocker rMgTX inhibited the mRNA expression of interferongamma, TNF-αand granzyme B in CD4~+ T cells in a dose-depend mode.Kv1.3channel on CD4~+ T cells especially on CD4~+CD28~(null) T cells, thus, may be suggestedas a potential therapeutic target for preventing atheromatous plaques fromdestablization.
Part 2 IKCa1 Potassium Channel Expression on CD4~+ andCD4~+CD28~(null) T Cells in Patients with Acute Coronary Syndrome andIts Implications
【Objective】To study the number changes of IKCa1 channel during activation onperipheral blood CD4~+ T cells and its subset CD4~+CD28~(null) in ACS patients and theeffects of IKCa1-specific channel blocker on effectors expression of activated CD4~+T cell, further discuss the implications of IKCa1 channel for atheromatous plaques.
【Methods】CD4+ T cells in all of and CD4~+CD28~(null) T cells in 12 of 24 ACSpatients were isolated from peripheral blood through magnetic cell sorting.Thewhole-cell IKCa1 currents of T cells above were recorded with patch-clamptechnique before and 3 days after activation by purified anti-human CD3 mAb.0.2, 1,5μmol/L of TRAM-34, a specific blocker of IKCa1 channel, were added separatelyto 3-day pre-activated CD4~+T cells, and 3 days' activation followed.The mRNAexpressions of interferon gamma, TNF-α, granzyme B in CD4~+ T cells were detectedby reverse transcription-PCR.
【Results】IKCa1 channels on each activated CD4~+ and CD4~+CD28~(null) T cell wererespectively proximately 9 and 8 times higher than those on each resting CD4~+ andCD4~+CD28~(null) T cell (439±161 vs.45±18, 497±174 vs.56±16 channels per cell aftervs.before activation respectively, both P<0.05).Both activated T cells had up totriple channel density, compared to their resting ones (both P<0.05).The numbersand density of IKCa1 channel were parallel between both T cells regardless ofactivation.The mRNA expression of interferon gamma, TNF-α, and granzyme Bwere down-regulated by all dose of TRAM-34, and differential expression of eachmRNA existed among varied dose of TRAM-34(P<0.01, respectively).The largerdose of rMgTX, the smaller expression of each mRNA.
【Conclusions】IKCa1 channel numbers and density increased significantly on peripheral blood CD4~+ and CD4~+CD28~(null) T cells after activation in ACS patients,and IKCa1-specific channel blocker TRAM-34 inhibited the mRNA expressions ofinterferon gamma, TNF-α, and granzyme B in activated CD4~+ T cells in adose-depend pattern.It may be indicated that IKCa1 channel on activated CD4~+ Tcells play an important role in atherosclerosis, and that IKCa1 channel blockers haveuse in therapeutic manipulation of atherosclerosis.
引文
[1] Matteson DR, Deutsch C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion[J]. Nature, 1984, 307: 468-71.
[2] DeCoursey TE, Chandy KG, Gupta S, et al. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?[J]. Nature, 1984, 307: 465-8.
[3] Attali B, Romey G, Honore E, et al. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes[J]. J Biol Chem, 1992, 267:8650-7.
[4] Folander K, Douglass J, Swanson R. Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1[J]. Genomics, 1994, 23: 295-6.
[5] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation[J]. Trends Pharmacol Sci, 2004, 25: 280-9.
[6] Panyi G, Possani LD, Rodriguez de la Vega RC, et al. K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression[J].Curr Pharm Des, 2006, 12: 2199-220.
[7] Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel[J]. Proc Natl Acad Sci USA, 1997, 94:11651-6.
[8] Joiner WJ, Wang LY, Tang MD, et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels [J]. Proc Natl Acad Sci USA, 1997, 94:11013-8.
[9] Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes [J]. J Biol Chem, 1997,272: 32723-6.
[10] Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCal potassium channel during T-cell activation. Molecular mechanism and functional consequences[J]. J Biol Chem, 2000, 275: 37137-49.
[11] Begenisich T, Nakamoto T, Ovitt CE, et al. Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4[J]. J Biol Chem, 2004,279:47681-7.
[12] Jensen BS, Hertz M, Christophersen P, et al. The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[13] Jensen BS, Strobaek D, Christophersen P, et al. Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel[J]. Am J Physiol, 1998, 275:C848-56.
[14] Jensen BS, Strobaek D, Olesen SP, et al. The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments?[J]. Curr Drug Targets, 2001,2:401-22.
[15] Vianna-Jorge R, Suarez-Kurtz G. Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders?[J]. BioDrugs, 2004, 18: 329-41.
[16] Grissmer S, Nguyen AN, Cahalan MD. Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology[J].J Gen Physiol,1993, 102:601-30.
[17] Panyi G, Varga Z, Gaspar Rh. Ion channels and lymphocyte activation[J].Immunol Lett, 2004, 92: 55-66.
[18] Hansson GK, Libby P, Schonbeck U, et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis[J]. Circ Res, 2002, 91: 281-91.
[19] Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques[J]. J Immunol, 2005, 174: 6509-17.
[20] Rossmann A, Henderson B, Heidecker B, et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire [J]. Exp Gerontol, 2008, 43: 229-37.
[21] Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1[J]. Arterioscler Thromb, 1992, 12: 206-11.
[22] Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogenesis[J]. Lupus, 2005, 14: 732-5,
[23] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions[J]. Proc Natl Acad Sci U S A, 2003, 100: 6658-63.
[24] Liuzzo G, Goronzy J J, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[25] Vallejo AN, Schirmer M, Weyand CM, et al. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways[J]. JImmunol, 2000, 165: 6301-7.
[26] De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism[J]. Circulation, 2006, 113: 640-6.
[27] Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina[J]. Circulation, 1999, 100:2135-9.
[28] Nakajima T, Schulte S, Warrin R. T-cell-mediated lysis of endothelial cells in acute coronary syndromes[J]. Circulation, 2002, 105: 570-5.
[29] Martens PB, Goronzy JJ, Schaid D, et al. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis[J]. Arthritis Rheum, 1997, 40: 1106-14.
[30] Weyand CM, Brandes JC, Schmidt D, et al. Functional properties of CD4+ CD28-T cells in the aging immune system[J]. Mech Ageing Dev, 1998, 102:131-47.
[31] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[32] 黄深，唐家荣，张存泰等．急性冠状动脉综合征患者的CD4~+CD28~(null)T淋巴细胞电压门控性Kv1.3钾通道数量增加[J]．中华心血管病杂志，2008，36：602-6．
[1] Matteson DR, Deutsch C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature, 1984, 307: 468-71.
[2] DeCoursey TE, Chandy KG, Gupta S, et al. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature, 1984, 307: 465-8.
[3] Attali B, Romey G, Honore E, et al. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes. J Biol Chem, 1992, 267:8650-7.
[4] Folander K, Douglass J, Swanson R. Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1. Genomics, 1994, 23: 295-6.
[5] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation. Trends Pharmacol Sci, 2004, 25: 280-9.
[6] Panyi G, Possani LD, Rodriguez de la Vega RC, et al. K+ channel blockers:novel tools to inhibit T cell activation leading to specific immunosuppression. Curr Pharm Des, 2006, 12: 2199-220.
[7] Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogenesis. Lupus,2005, 14: 732-5.
[8] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. Proc Natl Acad Sci USA, 2003, 100:6658-63.
[9] Martens PB, Goronzy JJ, Schaid D, et al. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum, 1997, 40: 1106-14.
[10] Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation, 1999, 100: 2135-9.
[11] 黄深,唐家荣,张存泰等.急性冠状动脉综合征患者的CD4~+CD28~(null)T淋 巴细胞电压门控性Kv1.3钾通道数量增加．中华心血管病杂志，2008，36：602-6．
[12] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation, 2000, 101: 2883-8.
[13] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会，中国循环杂志编辑委员会．急性心肌梗死诊断和治疗指南．中华心血管病杂志，2001，29：710-25．
[14] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会．不稳定性心绞痛诊断和治疗建议．中华心血管病杂志，2000 28：409-12．
[15] Kalman K, Pennington MW, Lanigan MD, et al. ShK-Dap22, a potentKv1.3-specific immunosuppressive polypeptide. J Biol Chem, 1998, 273:32697-707.
[16] Wulff H, Calabresi PA, Allie R, et al. The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. J Clin Invest, 2003, 111: 1703-13.
[17] Wulff H, Knaus HG, Pennington M, et al. K+ channel expression during B cell differentiation: implications for immunomodulation and autoimmunity. J Immunol, 2004, 173: 776-86.
[18] Vianna-Jorge R, Suarez-Kurtz G. Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders? BioDrugs, 2004, 18: 329-41.
[19] Vallejo AN, Schirmer M, Weyand CM, et al. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. J Immunol, 2000, 165: 6301-7.
[20] De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation, 2006, 113: 640-6.
[21] Nakajima T, Schulte S, Warrin R. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation, 2002, 105: 570-5.
[22] Levite M, Cahalon L, Peretz A, et al. Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and betal integrins. J Exp Med, 2000, 191: 1167-76.
[23] 徐仁德．CD4~+CD28~(null)T淋巴细胞Kv1.3和IKCa1通道作为急性冠脉综合征治疗靶点的研究(待发表)．
[24] 郭丽芬，张存泰，吴杰等．急性冠状动脉综合征患者淋巴细胞电压依赖性钾通道的变化．中华心血管病杂志，2007，35：818-21．
[1] Hansson GK, Libby P, Schonbeck U, et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis[J]. Circ Res, 2002, 91: 281-91.
[2] Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques[J]. J Immunol, 2005, 174: 6509-17.
[3] Rossmann A, Henderson B, Heidecker B, et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire[J]. Exp Gerontol, 2008, 43: 229-37.
[4] Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1[J]. Arterioscler Thromb, 1992, 12: 206-11.
[5] Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogenesis[J]. Lupus, 2005, 14: 732-5.
[6] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions[J]. Proc Natl Acad Sci U S A, 2003, 100: 6658-63.
[7] Grossman WJ, Verbsky JW, Tollefsen BL, et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells[J]. Blood, 2004, 104: 2840-8.
[8] Baidya SG, Zeng QT. Helper T cells and atherosclerosis: the cytokine web[J]. Postgrad Med J, 2005, 81: 746-52.
[9] Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice[J]. J Clin Invest, 1997, 99: 2752-61.
[10] Koga M, Kai H, Yasukawa H, et al. Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice[J]. Circ Res, 2007, 101: 348-56.
[11] Ohta H, Wada H, Niwa T, et al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice[J].Atherosclerosis, 2005, 180: 11-7.
[12] Bryl E, Vallejo AN, Weyand CM, et al. Down-regulation of CD28 expression by TNF-alpha[J]. J Immunol, 2001, 167: 3231-8.
[13] Rizzello V, Liuzzo G, Brugaletta S, et al. Modulation of CD4(+)CD28null T lymphocytes by tumor necrosis factor-alpha blockade in patients with unstable angina[J]. Circulation, 2006, 113: 2272-7.
[14] Choy JC, McDonald PC, Suarez AC, et al. Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity[J]. Mod Pathol, 2003, 16: 460-70.
[15] Choy JC, Hung VH, Hunter AL, et al. Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation[J]. Arterioscler Thromb Vasc Biol, 2004, 24: 2245-50.
[16] Chamberlain CM, Granville DJ. The role of Granzyme B in atheromatous diseases[J]. Can J Physiol Pharmacol, 2007, 85: 89-95.
[1] Jensen BS, Strobaek D, Christophersen P, et al. Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel[J]. Am J Physiol, 1998, 275: C848-56.
[2] Jensen BS, Hertz M, Christophersen P, et al. The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[3] Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel[J]. Proc Natl Acad Sci U S A, 1997, 94: 11651-6.
[4] Joiner WJ, Wang LY, Tang MD, et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels[J]. Proc Natl Acad Sci U S A, 1997, 94: 11013-8.
[5] Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes[J]. J Biol Chem, 1997, 272: 32723-6.
[6] Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCal potassium channel during T-cell activation. Molecular mechanism and functional consequences[J]. J Biol Chem, 2000, 275: 37137-49.
[7] Begenisich T, Nakamoto T, Ovitt CE, et al. Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4[J]. J Biol Chem, 2004, 279: 47681-7.
[8] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation[J]. Trends Pharmacol Sci, 2004, 25: 280-9.
[9] Jensen BS, Strobaek D, Olesen SP, et al. The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments?[J]. Curr Drug Targets, 2001, 2: 401-22.
[10] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions[J]. Proc Natl Acad Sci U S A, 2003, 100: 6658-63.
[11] Vallejo AN, Schirmer M, Weyand CM, et al. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways[J]. J Immunol, 2000, 165: 6301-7.
[12] De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism[J]. Circulation, 2006, 113: 640-6.
[13] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[14] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会，中国循环杂志编辑委员会．急性心肌梗死诊断和治疗指南[J]．中华心血管病杂志，2001，29：710-25．
[15] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会．不稳定性 心绞痛诊断和治疗建议[J].中华心血管病杂志,2000 28: 409-12.
[16] Wulff H, Calabresi PA, Allie R, et al.The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS[J]. J Clin Invest, 2003, 111:1703-13.
[17] Wulff H, Knaus HG, Pennington M, et al. K+ channel expression during B cell differentiation: implications for immunomodulation and autoimmunity [J]. J Immunol, 2004, 173: 776-86.
[18] Beeton C, Wulff H, Barbaria J, et al. Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis[J]. Proc Natl Acad Sci USA, 2001, 98: 13942-7.
[19] Thewissen M, Somers V, Hellings N, et al. CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation[J]. J Immunol, 2007, 179: 6514-23.
[20] Zal B, Baboonian C, Kaski JC. Autoreactive CD4+ CD28- T cells and acute coronary syndromes[J]. Arterioscler Thromb Vase Biol, 2007, 27: el8; author reply e9.
[21] Nakajima T, Goek O, Zhang X, et al. De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes[J]. Circ Res, 2003, 93: 106-13.
[22] Martens PB, Goronzy JJ, Schaid D, et al. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis[J]. Arthritis Rheum, 1997, 40: 1106-14.
[23] Weyand CM, Brandes JC, Schmidt D, et al. Functional properties of CD4+ CD28- T cells in the aging immune system[J]. Mech Ageing Dev, 1998, 102: 131-47.
[24] Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina[J]. Circulation, 1999, 100: 2135-9.
[25] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[26] 黄深，唐家荣，张存泰等．急性冠状动脉综合征患者的CD4~+CD28~(null)T淋巴细胞电压门控性Kv1.3钾通道数量增加[J]．中华心血管病杂志，2008，36：602-6．
[27] Shaw G, Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation[J]. Cell, 1986, 46: 659-67.
[28] Akashi M, Shaw G, Hachiya M, et al. Number and location of AUUUA motifs: role in regulating transiently expressed RNAs[J]. Blood, 1994, 83: 3182-7.
[29] Wymore RS, Negulescu D, Kinoshita K, et al. Characterization of the transcription unit of mouse Kv1.4, a voltage-gated potassium channel gene[J]. J Biol Chem, 1996, 271: 15629-34.
[1] Jensen BS, Strobaek D, Christophersen P, et al. Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel[J]. Am J Physiol, 1998, 275: C848-56.
[2] Jensen BS, Hertz M, Christophersen P, et al. The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[3] Baidya SG, Zeng QT. Helper T cells and atherosclerosis: the cytokine web[J].Postgrad Med J, 2005, 81: 746-52.
[4] Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice[J]. J Clin Invest, 1997, 99: 2752-61.
[5] Koga M, Kai H, Yasukawa H, et al. Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice[J].CircRes, 2007, 101:348-56.
[6] Branen L, Hovgaard L, Nitulescu M, et al. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice[J].Arterioscler Thromb Vase Biol, 2004, 24: 2137-42.
[7] Ohta H, Wada H, Niwa T, et al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice[J]. Atherosclerosis, 2005, 180: 11-7.
[8] Grossman WJ, Verbsky JW, Tollefsen BL, et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells [J]. Blood, 2004, 104: 2840-8.
[9] Choy JC, Hung VH, Hunter AL, et al. Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation[J]. Arterioscler Thromb Vase Biol, 2004, 24: 2245-50.
[10] Chamberlain CM, Granville DJ. The role of Granzyme B in atheromatous diseases[J]. Can J Physiol Pharmacol, 2007, 85: 89-95.
[1] Stuhmer W, Ruppersberg JP, Schroter KH, et al. Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain[J]. EMBO J,1989, 8: 3235-44.
[2] Chandy KG, Williams CB, Spencer RH, et al. A family of three mouse potassium channel genes with intronless coding regions[J]. Science, 1990, 247: 973-5.
[3] Douglass J, Osborne PB, Cai YC, et al. Characterization and functional expression of a rat genomic DNA clone encoding a lymphocyte potassium channel[J]. J Immunol, 1990, 144: 4841-50.
[4] Grissmer S, Dethlefs B, Wasmuth JJ, et al. Expression and chromosomal localization of a lymphocyte K+ channel gene[J]. Proc Natl Acad Sci USA, 1990,87:9411-5.
[5] Swanson R, Marshall J, Smith JS, et al. Cloning and expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain[J].Neuron, 1990,4:929-39.
[6] Philipson LH, Hice RE, Schaefer K, et al. Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel[J]. Proc Natl Acad Sci U S A,1991, 88: 53-7.
[7] Attali B, Romey G, Honore E, et al. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes [J]. J Biol Chem, 1992, 267:8650-7.
[8] Cai YC, Osborne PB, North RA, et al. Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel[J]. DNA Cell Biol, 1992, 11: 163-72.
[9] Matteson DR, Deutsch C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion[J]. Nature, 1984, 307: 468-71.
[10] DeCoursey TE, Chandy KG, Gupta S, et al. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?[J]. Nature, 1984, 307: 465-8.
[11] Folander K, Douglass J, Swanson R. Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1[J]. Genomics, 1994, 23: 295-6.
[12] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation[J]. Trends Pharmacol Sci, 2004, 25: 280-9.
[13] Panyi G, Possani LD, Rodriguez de la Vega RC, et al. K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression[J].Curr Pharm Des, 2006, 12: 2199-220.
[14] Jiang Y, Lee A, Chen J, et al. X-ray structure of a voltage-dependent K+channel[J]. Nature, 2003, 423: 33-41.
[15] Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel[J]. Proc Natl Acad Sci USA, 1997, 94:11651-6.
[16] Joiner WJ, Wang LY, Tang MD, et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels[J]. Proc Natl Acad Sci USA, 1997, 94:11013-8.
[17] Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes[J]. J Biol Chem, 1997,272:32723-6.
[18] Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCal potassium channel during T-cell activation. Molecular mechanism and functional consequences[J]. J Biol Chem, 2000, 275: 37137-49.
[19] Begenisich T, Nakamoto T, Ovitt CE, et al. Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4[J]. J Biol Chem,2004,279:47681-7.
[20] Jensen BS, Hertz M, Christ ophersen P, et al. The Ca2+-activated K+ channel of intermediate conductances possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[21] Verheugen JA, Vijverberg HP, Oortgiesen M, et al. Voltage-gated and Ca(2+)-activated K+ channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium[J]. J Gen Physiol, 1995, 105: 765-94.
[22] Grissmer S, Nguyen AN, Cahalan MD. Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology [J]. J Gen Physiol, 1993, 102: 601-30.
[23] Panyi G, Varga Z, Gaspar Rh. Ion channels and lymphocyte activation[J]. Immunol Lett, 2004, 92: 55-66.
[24] Vianna-Jorge R, Suarez-Kurtz G. Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders?[J]. BioDrugs, 2004, 18: 329-41.
[25] Beeton C, Wulff H, Singh S, et al. A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes[J]. J Biol Chem, 2003, 278: 9928-37.
[26] Michne WF, Guiles JW, Treasurywala AM, et al. Novel inhibitors of potassium ion channels on human T lymphocytes [J]. J Med Chem, 1995, 38:1877-83.
[27] Hill RJ, Grant AM, Volberg W, et al. WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes [J]. Mol Pharmacol, 1995, 48: 98-104.
[28] Nguyen A, Kath JC, Hanson DC, et al. Novel nonpeptide agents potently block the C-type inactivated conformation of Kvl.3 and suppress T cell activation[J].Mol Pharmacol, 1996, 50: 1672-9.
[29] Hanson DC, Nguyen A, Mather RJ, et al. UK-78,282, a novel piperidine compound that potently blocks the Kvl.3 voltage-gated potassium channel and inhibits human T cell activation[J]. Br J Pharmacol, 1999, 126: 1707-16.
[30] Felix JP, Bugianesi RM, Schmalhofer WA, et al. Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kvl.3[J]. Biochemistry, 1999, 38:4922-30.
[31] Wanner SG, Glossmann H, Knaus HG, et al. WIN 17317-3, a new high-affinity probe for voltage-gated sodium channels[J]. Biochemistry, 1999, 38:11137-46.
[32] Vianna-Jorge R, Oliveira CF, Ponte CG, et al. WIN 17317-3 blocks Ca2+-activated K+ channels and enhances motility of guinea-pig detrusor muscle[J].Eur J Pharmacol, 2001, 428: 45-9.
[33] Vianna-Jorge R, Oliveira CF, Garcia ML, et al. Correolide, a nor-triterpenoid blocker of Shaker-type Kv1 channels elicits twitches in guinea-pig ileum by stimulating the enteric nervous system and enhancing neurotransmitter release[J]. Br J Pharmacol, 2000, 131: 772-8.
[34] Vianna-Jorge R, Oliveira CF, Garcia ML, et al. Shaker-type Kvl channel blockers increase the peristaltic activity of guinea-pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system[J]. Br J Pharmacol, 2003, 138: 57-62.
[35] Kohler R, Wulff H, Eichler I, et al. Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis[J]. Circulation, 2003, 108: 1119-25.
[36] Stocker JW, De Franceschi L, McNaughton-Smith GA, et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice[J]. Blood, 2003, 101: 2412-8.
[37] Beeton C, Wulff H, Barbaria J, et al. Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis[J]. Proc Natl Acad Sci U S A, 2001, 98: 13942-7.
[38] Wulff H, Calabresi PA, Allie R, et al. The voltage-gated Kvl.3 K(+) channel in effector memory T cells as new target for MS[J]. J Clin Invest, 2003, 111: 1703-13.
[39] Koo GC, Blake JT, Talento A, et al. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo[J]. J Immunol, 1997, 158: 5120-8.
[40] Koo GC, Blake JT, Shah K, et al. Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels[J]. Cell Immunol, 1999, 197: 99-107.
[41] Beeton C, Barbaria J, Giraud P, et al. Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation[J]. J Immunol, 2001, 166: 936-44.
[42] Hansson GK, Libby P, Schonbeck U, et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis [J]. Circ Res, 2002, 91: 281-91.
[43] Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques [J]. J Immunol, 2005, 174: 6509-17.
[44] Rossmann A, Henderson B, Heidecker B, et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire[J]. Exp Gerontol, 2008, 43: 229-37.
[2] DeCoursey TE, Chandy KG, Gupta S, et al. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?[J]. Nature, 1984, 307: 465-8.
[3] Attali B, Romey G, Honore E, et al. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes[J]. J Biol Chem, 1992, 267:8650-7.
[4] Folander K, Douglass J, Swanson R. Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1[J]. Genomics, 1994, 23: 295-6.
[5] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation[J]. Trends Pharmacol Sci, 2004, 25: 280-9.
[6] Panyi G, Possani LD, Rodriguez de la Vega RC, et al. K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression[J].Curr Pharm Des, 2006, 12: 2199-220.
[7] Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel[J]. Proc Natl Acad Sci USA, 1997, 94:11651-6.
[8] Joiner WJ, Wang LY, Tang MD, et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels [J]. Proc Natl Acad Sci USA, 1997, 94:11013-8.
[9] Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes [J]. J Biol Chem, 1997,272: 32723-6.
[10] Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCal potassium channel during T-cell activation. Molecular mechanism and functional consequences[J]. J Biol Chem, 2000, 275: 37137-49.
[11] Begenisich T, Nakamoto T, Ovitt CE, et al. Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4[J]. J Biol Chem, 2004,279:47681-7.
[12] Jensen BS, Hertz M, Christophersen P, et al. The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[13] Jensen BS, Strobaek D, Christophersen P, et al. Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel[J]. Am J Physiol, 1998, 275:C848-56.
[14] Jensen BS, Strobaek D, Olesen SP, et al. The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments?[J]. Curr Drug Targets, 2001,2:401-22.
[15] Vianna-Jorge R, Suarez-Kurtz G. Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders?[J]. BioDrugs, 2004, 18: 329-41.
[16] Grissmer S, Nguyen AN, Cahalan MD. Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology[J].J Gen Physiol,1993, 102:601-30.
[17] Panyi G, Varga Z, Gaspar Rh. Ion channels and lymphocyte activation[J].Immunol Lett, 2004, 92: 55-66.
[18] Hansson GK, Libby P, Schonbeck U, et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis[J]. Circ Res, 2002, 91: 281-91.
[19] Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques[J]. J Immunol, 2005, 174: 6509-17.
[20] Rossmann A, Henderson B, Heidecker B, et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire [J]. Exp Gerontol, 2008, 43: 229-37.
[21] Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1[J]. Arterioscler Thromb, 1992, 12: 206-11.
[22] Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogenesis[J]. Lupus, 2005, 14: 732-5,
[23] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions[J]. Proc Natl Acad Sci U S A, 2003, 100: 6658-63.
[24] Liuzzo G, Goronzy J J, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[25] Vallejo AN, Schirmer M, Weyand CM, et al. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways[J]. JImmunol, 2000, 165: 6301-7.
[26] De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism[J]. Circulation, 2006, 113: 640-6.
[27] Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina[J]. Circulation, 1999, 100:2135-9.
[28] Nakajima T, Schulte S, Warrin R. T-cell-mediated lysis of endothelial cells in acute coronary syndromes[J]. Circulation, 2002, 105: 570-5.
[29] Martens PB, Goronzy JJ, Schaid D, et al. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis[J]. Arthritis Rheum, 1997, 40: 1106-14.
[30] Weyand CM, Brandes JC, Schmidt D, et al. Functional properties of CD4+ CD28-T cells in the aging immune system[J]. Mech Ageing Dev, 1998, 102:131-47.
[31] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[32] 黄深，唐家荣，张存泰等．急性冠状动脉综合征患者的CD4~+CD28~(null)T淋巴细胞电压门控性Kv1.3钾通道数量增加[J]．中华心血管病杂志，2008，36：602-6．
[1] Matteson DR, Deutsch C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion. Nature, 1984, 307: 468-71.
[2] DeCoursey TE, Chandy KG, Gupta S, et al. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature, 1984, 307: 465-8.
[3] Attali B, Romey G, Honore E, et al. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes. J Biol Chem, 1992, 267:8650-7.
[4] Folander K, Douglass J, Swanson R. Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1. Genomics, 1994, 23: 295-6.
[5] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation. Trends Pharmacol Sci, 2004, 25: 280-9.
[6] Panyi G, Possani LD, Rodriguez de la Vega RC, et al. K+ channel blockers:novel tools to inhibit T cell activation leading to specific immunosuppression. Curr Pharm Des, 2006, 12: 2199-220.
[7] Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogenesis. Lupus,2005, 14: 732-5.
[8] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. Proc Natl Acad Sci USA, 2003, 100:6658-63.
[9] Martens PB, Goronzy JJ, Schaid D, et al. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis. Arthritis Rheum, 1997, 40: 1106-14.
[10] Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation, 1999, 100: 2135-9.
[11] 黄深,唐家荣,张存泰等.急性冠状动脉综合征患者的CD4~+CD28~(null)T淋 巴细胞电压门控性Kv1.3钾通道数量增加．中华心血管病杂志，2008，36：602-6．
[12] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation, 2000, 101: 2883-8.
[13] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会，中国循环杂志编辑委员会．急性心肌梗死诊断和治疗指南．中华心血管病杂志，2001，29：710-25．
[14] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会．不稳定性心绞痛诊断和治疗建议．中华心血管病杂志，2000 28：409-12．
[15] Kalman K, Pennington MW, Lanigan MD, et al. ShK-Dap22, a potentKv1.3-specific immunosuppressive polypeptide. J Biol Chem, 1998, 273:32697-707.
[16] Wulff H, Calabresi PA, Allie R, et al. The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. J Clin Invest, 2003, 111: 1703-13.
[17] Wulff H, Knaus HG, Pennington M, et al. K+ channel expression during B cell differentiation: implications for immunomodulation and autoimmunity. J Immunol, 2004, 173: 776-86.
[18] Vianna-Jorge R, Suarez-Kurtz G. Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders? BioDrugs, 2004, 18: 329-41.
[19] Vallejo AN, Schirmer M, Weyand CM, et al. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways. J Immunol, 2000, 165: 6301-7.
[20] De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation, 2006, 113: 640-6.
[21] Nakajima T, Schulte S, Warrin R. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation, 2002, 105: 570-5.
[22] Levite M, Cahalon L, Peretz A, et al. Extracellular K(+) and opening of voltage-gated potassium channels activate T cell integrin function: physical and functional association between Kv1.3 channels and betal integrins. J Exp Med, 2000, 191: 1167-76.
[23] 徐仁德．CD4~+CD28~(null)T淋巴细胞Kv1.3和IKCa1通道作为急性冠脉综合征治疗靶点的研究(待发表)．
[24] 郭丽芬，张存泰，吴杰等．急性冠状动脉综合征患者淋巴细胞电压依赖性钾通道的变化．中华心血管病杂志，2007，35：818-21．
[1] Hansson GK, Libby P, Schonbeck U, et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis[J]. Circ Res, 2002, 91: 281-91.
[2] Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques[J]. J Immunol, 2005, 174: 6509-17.
[3] Rossmann A, Henderson B, Heidecker B, et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire[J]. Exp Gerontol, 2008, 43: 229-37.
[4] Stemme S, Holm J, Hansson GK. T lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1[J]. Arterioscler Thromb, 1992, 12: 206-11.
[5] Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogenesis[J]. Lupus, 2005, 14: 732-5.
[6] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions[J]. Proc Natl Acad Sci U S A, 2003, 100: 6658-63.
[7] Grossman WJ, Verbsky JW, Tollefsen BL, et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells[J]. Blood, 2004, 104: 2840-8.
[8] Baidya SG, Zeng QT. Helper T cells and atherosclerosis: the cytokine web[J]. Postgrad Med J, 2005, 81: 746-52.
[9] Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice[J]. J Clin Invest, 1997, 99: 2752-61.
[10] Koga M, Kai H, Yasukawa H, et al. Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice[J]. Circ Res, 2007, 101: 348-56.
[11] Ohta H, Wada H, Niwa T, et al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice[J].Atherosclerosis, 2005, 180: 11-7.
[12] Bryl E, Vallejo AN, Weyand CM, et al. Down-regulation of CD28 expression by TNF-alpha[J]. J Immunol, 2001, 167: 3231-8.
[13] Rizzello V, Liuzzo G, Brugaletta S, et al. Modulation of CD4(+)CD28null T lymphocytes by tumor necrosis factor-alpha blockade in patients with unstable angina[J]. Circulation, 2006, 113: 2272-7.
[14] Choy JC, McDonald PC, Suarez AC, et al. Granzyme B in atherosclerosis and transplant vascular disease: association with cell death and atherosclerotic disease severity[J]. Mod Pathol, 2003, 16: 460-70.
[15] Choy JC, Hung VH, Hunter AL, et al. Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation[J]. Arterioscler Thromb Vasc Biol, 2004, 24: 2245-50.
[16] Chamberlain CM, Granville DJ. The role of Granzyme B in atheromatous diseases[J]. Can J Physiol Pharmacol, 2007, 85: 89-95.
[1] Jensen BS, Strobaek D, Christophersen P, et al. Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel[J]. Am J Physiol, 1998, 275: C848-56.
[2] Jensen BS, Hertz M, Christophersen P, et al. The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[3] Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel[J]. Proc Natl Acad Sci U S A, 1997, 94: 11651-6.
[4] Joiner WJ, Wang LY, Tang MD, et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels[J]. Proc Natl Acad Sci U S A, 1997, 94: 11013-8.
[5] Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes[J]. J Biol Chem, 1997, 272: 32723-6.
[6] Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCal potassium channel during T-cell activation. Molecular mechanism and functional consequences[J]. J Biol Chem, 2000, 275: 37137-49.
[7] Begenisich T, Nakamoto T, Ovitt CE, et al. Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4[J]. J Biol Chem, 2004, 279: 47681-7.
[8] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation[J]. Trends Pharmacol Sci, 2004, 25: 280-9.
[9] Jensen BS, Strobaek D, Olesen SP, et al. The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments?[J]. Curr Drug Targets, 2001, 2: 401-22.
[10] Benagiano M, Azzurri A, Ciervo A, et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions[J]. Proc Natl Acad Sci U S A, 2003, 100: 6658-63.
[11] Vallejo AN, Schirmer M, Weyand CM, et al. Clonality and longevity of CD4+CD28null T cells are associated with defects in apoptotic pathways[J]. J Immunol, 2000, 165: 6301-7.
[12] De Palma R, Del Galdo F, Abbate G, et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism[J]. Circulation, 2006, 113: 640-6.
[13] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[14] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会，中国循环杂志编辑委员会．急性心肌梗死诊断和治疗指南[J]．中华心血管病杂志，2001，29：710-25．
[15] 中华医学会心血管病学分会，中华心血管病杂志编辑委员会．不稳定性 心绞痛诊断和治疗建议[J].中华心血管病杂志,2000 28: 409-12.
[16] Wulff H, Calabresi PA, Allie R, et al.The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS[J]. J Clin Invest, 2003, 111:1703-13.
[17] Wulff H, Knaus HG, Pennington M, et al. K+ channel expression during B cell differentiation: implications for immunomodulation and autoimmunity [J]. J Immunol, 2004, 173: 776-86.
[18] Beeton C, Wulff H, Barbaria J, et al. Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis[J]. Proc Natl Acad Sci USA, 2001, 98: 13942-7.
[19] Thewissen M, Somers V, Hellings N, et al. CD4+CD28null T cells in autoimmune disease: pathogenic features and decreased susceptibility to immunoregulation[J]. J Immunol, 2007, 179: 6514-23.
[20] Zal B, Baboonian C, Kaski JC. Autoreactive CD4+ CD28- T cells and acute coronary syndromes[J]. Arterioscler Thromb Vase Biol, 2007, 27: el8; author reply e9.
[21] Nakajima T, Goek O, Zhang X, et al. De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes[J]. Circ Res, 2003, 93: 106-13.
[22] Martens PB, Goronzy JJ, Schaid D, et al. Expansion of unusual CD4+ T cells in severe rheumatoid arthritis[J]. Arthritis Rheum, 1997, 40: 1106-14.
[23] Weyand CM, Brandes JC, Schmidt D, et al. Functional properties of CD4+ CD28- T cells in the aging immune system[J]. Mech Ageing Dev, 1998, 102: 131-47.
[24] Liuzzo G, Kopecky SL, Frye RL, et al. Perturbation of the T-cell repertoire in patients with unstable angina[J]. Circulation, 1999, 100: 2135-9.
[25] Liuzzo G, Goronzy JJ, Yang H, et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes[J]. Circulation, 2000, 101: 2883-8.
[26] 黄深，唐家荣，张存泰等．急性冠状动脉综合征患者的CD4~+CD28~(null)T淋巴细胞电压门控性Kv1.3钾通道数量增加[J]．中华心血管病杂志，2008，36：602-6．
[27] Shaw G, Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation[J]. Cell, 1986, 46: 659-67.
[28] Akashi M, Shaw G, Hachiya M, et al. Number and location of AUUUA motifs: role in regulating transiently expressed RNAs[J]. Blood, 1994, 83: 3182-7.
[29] Wymore RS, Negulescu D, Kinoshita K, et al. Characterization of the transcription unit of mouse Kv1.4, a voltage-gated potassium channel gene[J]. J Biol Chem, 1996, 271: 15629-34.
[1] Jensen BS, Strobaek D, Christophersen P, et al. Characterization of the cloned human intermediate-conductance Ca2+-activated K+ channel[J]. Am J Physiol, 1998, 275: C848-56.
[2] Jensen BS, Hertz M, Christophersen P, et al. The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[3] Baidya SG, Zeng QT. Helper T cells and atherosclerosis: the cytokine web[J].Postgrad Med J, 2005, 81: 746-52.
[4] Gupta S, Pablo AM, Jiang X, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice[J]. J Clin Invest, 1997, 99: 2752-61.
[5] Koga M, Kai H, Yasukawa H, et al. Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice[J].CircRes, 2007, 101:348-56.
[6] Branen L, Hovgaard L, Nitulescu M, et al. Inhibition of tumor necrosis factor-alpha reduces atherosclerosis in apolipoprotein E knockout mice[J].Arterioscler Thromb Vase Biol, 2004, 24: 2137-42.
[7] Ohta H, Wada H, Niwa T, et al. Disruption of tumor necrosis factor-alpha gene diminishes the development of atherosclerosis in ApoE-deficient mice[J]. Atherosclerosis, 2005, 180: 11-7.
[8] Grossman WJ, Verbsky JW, Tollefsen BL, et al. Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells [J]. Blood, 2004, 104: 2840-8.
[9] Choy JC, Hung VH, Hunter AL, et al. Granzyme B induces smooth muscle cell apoptosis in the absence of perforin: involvement of extracellular matrix degradation[J]. Arterioscler Thromb Vase Biol, 2004, 24: 2245-50.
[10] Chamberlain CM, Granville DJ. The role of Granzyme B in atheromatous diseases[J]. Can J Physiol Pharmacol, 2007, 85: 89-95.
[1] Stuhmer W, Ruppersberg JP, Schroter KH, et al. Molecular basis of functional diversity of voltage-gated potassium channels in mammalian brain[J]. EMBO J,1989, 8: 3235-44.
[2] Chandy KG, Williams CB, Spencer RH, et al. A family of three mouse potassium channel genes with intronless coding regions[J]. Science, 1990, 247: 973-5.
[3] Douglass J, Osborne PB, Cai YC, et al. Characterization and functional expression of a rat genomic DNA clone encoding a lymphocyte potassium channel[J]. J Immunol, 1990, 144: 4841-50.
[4] Grissmer S, Dethlefs B, Wasmuth JJ, et al. Expression and chromosomal localization of a lymphocyte K+ channel gene[J]. Proc Natl Acad Sci USA, 1990,87:9411-5.
[5] Swanson R, Marshall J, Smith JS, et al. Cloning and expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain[J].Neuron, 1990,4:929-39.
[6] Philipson LH, Hice RE, Schaefer K, et al. Sequence and functional expression in Xenopus oocytes of a human insulinoma and islet potassium channel[J]. Proc Natl Acad Sci U S A,1991, 88: 53-7.
[7] Attali B, Romey G, Honore E, et al. Cloning, functional expression, and regulation of two K+ channels in human T lymphocytes [J]. J Biol Chem, 1992, 267:8650-7.
[8] Cai YC, Osborne PB, North RA, et al. Characterization and functional expression of genomic DNA encoding the human lymphocyte type n potassium channel[J]. DNA Cell Biol, 1992, 11: 163-72.
[9] Matteson DR, Deutsch C. K channels in T lymphocytes: a patch clamp study using monoclonal antibody adhesion[J]. Nature, 1984, 307: 468-71.
[10] DeCoursey TE, Chandy KG, Gupta S, et al. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?[J]. Nature, 1984, 307: 465-8.
[11] Folander K, Douglass J, Swanson R. Confirmation of the assignment of the gene encoding Kv1.3, a voltage-gated potassium channel (KCNA3) to the proximal short arm of human chromosome 1[J]. Genomics, 1994, 23: 295-6.
[12] George Chandy K, Wulff H, Beeton C, et al. K+ channels as targets for specific immunomodulation[J]. Trends Pharmacol Sci, 2004, 25: 280-9.
[13] Panyi G, Possani LD, Rodriguez de la Vega RC, et al. K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression[J].Curr Pharm Des, 2006, 12: 2199-220.
[14] Jiang Y, Lee A, Chen J, et al. X-ray structure of a voltage-dependent K+channel[J]. Nature, 2003, 423: 33-41.
[15] Ishii TM, Silvia C, Hirschberg B, et al. A human intermediate conductance calcium-activated potassium channel[J]. Proc Natl Acad Sci USA, 1997, 94:11651-6.
[16] Joiner WJ, Wang LY, Tang MD, et al. hSK4, a member of a novel subfamily of calcium-activated potassium channels[J]. Proc Natl Acad Sci USA, 1997, 94:11013-8.
[17] Logsdon NJ, Kang J, Togo JA, et al. A novel gene, hKCa4, encodes the calcium-activated potassium channel in human T lymphocytes[J]. J Biol Chem, 1997,272:32723-6.
[18] Ghanshani S, Wulff H, Miller MJ, et al. Up-regulation of the IKCal potassium channel during T-cell activation. Molecular mechanism and functional consequences[J]. J Biol Chem, 2000, 275: 37137-49.
[19] Begenisich T, Nakamoto T, Ovitt CE, et al. Physiological roles of the intermediate conductance, Ca2+-activated potassium channel Kcnn4[J]. J Biol Chem,2004,279:47681-7.
[20] Jensen BS, Hertz M, Christ ophersen P, et al. The Ca2+-activated K+ channel of intermediate conductances possible target for immune suppression[J]. Expert Opin Ther Targets, 2002, 6: 623-36.
[21] Verheugen JA, Vijverberg HP, Oortgiesen M, et al. Voltage-gated and Ca(2+)-activated K+ channels in intact human T lymphocytes. Noninvasive measurements of membrane currents, membrane potential, and intracellular calcium[J]. J Gen Physiol, 1995, 105: 765-94.
[22] Grissmer S, Nguyen AN, Cahalan MD. Calcium-activated potassium channels in resting and activated human T lymphocytes. Expression levels, calcium dependence, ion selectivity, and pharmacology [J]. J Gen Physiol, 1993, 102: 601-30.
[23] Panyi G, Varga Z, Gaspar Rh. Ion channels and lymphocyte activation[J]. Immunol Lett, 2004, 92: 55-66.
[24] Vianna-Jorge R, Suarez-Kurtz G. Potassium channels in T lymphocytes: therapeutic targets for autoimmune disorders?[J]. BioDrugs, 2004, 18: 329-41.
[25] Beeton C, Wulff H, Singh S, et al. A novel fluorescent toxin to detect and investigate Kv1.3 channel up-regulation in chronically activated T lymphocytes[J]. J Biol Chem, 2003, 278: 9928-37.
[26] Michne WF, Guiles JW, Treasurywala AM, et al. Novel inhibitors of potassium ion channels on human T lymphocytes [J]. J Med Chem, 1995, 38:1877-83.
[27] Hill RJ, Grant AM, Volberg W, et al. WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes [J]. Mol Pharmacol, 1995, 48: 98-104.
[28] Nguyen A, Kath JC, Hanson DC, et al. Novel nonpeptide agents potently block the C-type inactivated conformation of Kvl.3 and suppress T cell activation[J].Mol Pharmacol, 1996, 50: 1672-9.
[29] Hanson DC, Nguyen A, Mather RJ, et al. UK-78,282, a novel piperidine compound that potently blocks the Kvl.3 voltage-gated potassium channel and inhibits human T cell activation[J]. Br J Pharmacol, 1999, 126: 1707-16.
[30] Felix JP, Bugianesi RM, Schmalhofer WA, et al. Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kvl.3[J]. Biochemistry, 1999, 38:4922-30.
[31] Wanner SG, Glossmann H, Knaus HG, et al. WIN 17317-3, a new high-affinity probe for voltage-gated sodium channels[J]. Biochemistry, 1999, 38:11137-46.
[32] Vianna-Jorge R, Oliveira CF, Ponte CG, et al. WIN 17317-3 blocks Ca2+-activated K+ channels and enhances motility of guinea-pig detrusor muscle[J].Eur J Pharmacol, 2001, 428: 45-9.
[33] Vianna-Jorge R, Oliveira CF, Garcia ML, et al. Correolide, a nor-triterpenoid blocker of Shaker-type Kv1 channels elicits twitches in guinea-pig ileum by stimulating the enteric nervous system and enhancing neurotransmitter release[J]. Br J Pharmacol, 2000, 131: 772-8.
[34] Vianna-Jorge R, Oliveira CF, Garcia ML, et al. Shaker-type Kvl channel blockers increase the peristaltic activity of guinea-pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system[J]. Br J Pharmacol, 2003, 138: 57-62.
[35] Kohler R, Wulff H, Eichler I, et al. Blockade of the intermediate-conductance calcium-activated potassium channel as a new therapeutic strategy for restenosis[J]. Circulation, 2003, 108: 1119-25.
[36] Stocker JW, De Franceschi L, McNaughton-Smith GA, et al. ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice[J]. Blood, 2003, 101: 2412-8.
[37] Beeton C, Wulff H, Barbaria J, et al. Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis[J]. Proc Natl Acad Sci U S A, 2001, 98: 13942-7.
[38] Wulff H, Calabresi PA, Allie R, et al. The voltage-gated Kvl.3 K(+) channel in effector memory T cells as new target for MS[J]. J Clin Invest, 2003, 111: 1703-13.
[39] Koo GC, Blake JT, Talento A, et al. Blockade of the voltage-gated potassium channel Kv1.3 inhibits immune responses in vivo[J]. J Immunol, 1997, 158: 5120-8.
[40] Koo GC, Blake JT, Shah K, et al. Correolide and derivatives are novel immunosuppressants blocking the lymphocyte Kv1.3 potassium channels[J]. Cell Immunol, 1999, 197: 99-107.
[41] Beeton C, Barbaria J, Giraud P, et al. Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation[J]. J Immunol, 2001, 166: 936-44.
[42] Hansson GK, Libby P, Schonbeck U, et al. Innate and adaptive immunity in the pathogenesis of atherosclerosis [J]. Circ Res, 2002, 91: 281-91.
[43] Benagiano M, D'Elios MM, Amedei A, et al. Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques [J]. J Immunol, 2005, 174: 6509-17.
[44] Rossmann A, Henderson B, Heidecker B, et al. T-cells from advanced atherosclerotic lesions recognize hHSP60 and have a restricted T-cell receptor repertoire[J]. Exp Gerontol, 2008, 43: 229-37.