原发性高血压患者血清中抗AT_1受体自身抗体的生物学效应及其产生机制研究
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摘要
第一部分原发性高血压患者中抗AT_1受体自身抗体刺激大鼠主动脉平滑肌细胞增殖及胞内信号分子研究
背景及目的：在妊高征和恶性高血压患者血清中检测到抗血管紧张素Ⅱ1型受体自身抗体(AT_1-AA)的存在，同时有研究表明该自身抗体有类似血管紧张素Ⅱ(AngⅡ)的激动样作用并参与高血压免疫发病机制形成。在此我们将进一步阐述该自身抗体其激动样效应的细胞内信号机制。
方法：大鼠主动脉细胞培养及鉴定。同时将收集原发性高血压病人血清经硫酸铵沉淀粗提、免疫亲和层析法纯化，ELISA检测其滴度后以1：40刺激细胞，并设立不同的处理组用BrdU法观察细胞增殖情况。经western印迹方法和电泳迁移率变动分析胞内信号分子激活及表达状况。
结果：在0～24h的平滑肌细胞增殖实验中，AT_1-AA组有类似于AngⅡ的作用。Western及EMSA显示AT_1-AA组中NF-κB和磷酸化的JAK2、STAT1和STAT3水平分别较空白对照组明显增强，而表达可相应被PDTC(NF-κB拮抗剂)、AT_1受体阻滞剂Losartan和JAK2特异性拮抗剂AG490明显抑制。同时，NF-κB和磷酸化的STAT1和STAT3表达分别在不同的时间梯度达高峰，且磷酸化STAT3的活化较STAT1更为明显。
结论：高血压病人血清中AT_1-AA确有类似血管紧张素Ⅱ致平滑肌细胞增殖激动样效应，并且在该效应中伴有NF-κB、JAK-STAT信号通路的活化。且不同于AngⅡ的是，胞内JAK-STAT途径中以STAT3活化为主。
第二部分原发性高血压患者中抗AT_1受体自身抗体产生与HLA基因多态性间的关联性研究
背景及目的：在妊高征、恶性高血压和原发性高血压患者血清中都可检测到抗血管紧张素Ⅱ1型受体自身抗体(AT_1-AA)的存在，然而其产生机制至今研究的甚少。本文主要分析其与免疫基因HLA多态性间的关联。
方法：入选394例原发性高血压病人和224例正常血压健康体检者，并通过ELISA检测自身抗体滴度。我们收集入选者一般临床资料，包括性别、年龄、体重指数、血压、吸烟及糖尿病情况。高血压和正常对照组分别按抗体阴性和阳性进行分组。通过PCR序列特异性引物法(PCR-SSP)进行HLA基因分型。
结果：13种HLA-DRB1基因型和7种HLA-DQB1基因型被检测。结果表明不同的HLA-DRB1和HLA-DQB1基因型在原发性高血压和正常人群中表达频率不同，且单倍型HLA-DQB1~*06-DRB1~*13是原发性高血压形成的独立危险因素(校正后P=0．014，OR 3．138，95％CI 1．259-7．819)。正常血压者中HLA-DRB1~*04和HLA-DRB1~*14基因型与AT_1-AA产生关联(分别P=0．001，OR 3．056，95％CI 1．562-5．974；P=0．033，OR2．528，95％CI 1．080-5．914)，同时高血压患者中基因型HLA-DRB1~*04也与AT_1-AA产生相关，以P＜0．1为检验水准则其P值经校正后仍存在统计学差异(校正后P=0．07，OR 1．629，95％CI0．954-2．780)。
结论：上述结果表明高血压患者和正常人血清中自身抗体形成具有不同的免疫遗传背景，同时阐明了环境因素血压和基因易感因素HLA-DRB1~*04等位基因型与AT_1-AA产生密切相关。
第三部分抗AT_1受体自身抗体与其受体基因AGTR1多态性的关联研究、及两者对药物Candesartan降压效应的影响
背景及目的：不同的个体对降压药AT_1受体拮抗剂(ARB)的反应存在较大的差异，同时AT_1-AA在高血压的发生法发展中起到重要的作用，因此我的目的研究其降压个体差异产生的原因即降压效应与AT_1受体基因AGTR1多态性、AT_1受体自身抗体间的是否存在一定的关联性。
方法：随机选取175名原发性高血压患者进行为期8周的Candesartan临床试验，并进行AT_1-AA阳性和阴性分组。收集其血样标本进行DNA提取并通过直接测序法对AGTR1基因中三个SNP位点rs1492078、rs5186和rs380400进行分型。通过ELISA法检测AT_1-AA滴度。
结果：结果显示Candesartan治疗后抗体阳性组和阴性组间舒张压下降程度无明显差异，而收缩压的下降抗体阳性组显著多于抗体阴性组(P=0．014，校正后P=0．050)。在抗体阴阳性分组后检测到单倍型[GAC]与AT_1-AA的产生负相关(校正后P=0．028OR0．342，95％CI0．131-0．890)，而三个SNP位点中单个点基因型与其自身抗体频率间无相关性。校正了年龄、性别和自身抗体对降压药物的影响后，rs5186(A/C)和单倍型[GCC]能显著增强Candesartan降收缩压效应(校正后分别P=0．028和P=0．026)，而单倍型[AAC]则显示能增强Candesartan降舒张压效应(校正后P=0．016)。
结论：AT_1-AA的产生可能与其受体基因AGTR1存在一定的关联性。而且，AT_1-AA与AGTR1基因多态性可能独立或共同影响Candesartan的降压效应。
PartⅠThe mechanism of signal transduction in rat VSMCproliferation induced by autoantibodies against angiotensin AT_1receptor from essential hypertensives
Background and objective:The autoantibodies against angiotension AT_1 receptor(AT_1-AA) have been discovered in the patients with malignant hypertensive,preeclampsiaand essential hypertension (EH).Some studies have demonstrated the autoantiboies areinvolved in the immunopathogenesis of hypertension and have an agonist-like activityeffect similar to angiotensinⅡ(AngⅡ).We further expound the mechanism of signaltransduction induced by autoantibodies against angiotensin AT_1 receptor fromhypertensives.
Methods:The rat VSMCs were cultured and identified.The autoantiboies against AT_1receptor were purified from sera of the primary hypertension patients by ammonium sulfateprecipitation and affinity chromatography.Then the AT_1-AA collected was detected byELISA and activated cells with 1:40 and judged the effect on rat VSMC proliferation bythe method of BrdU incorporation in different treatment groups.The activation of signalingmolecules were detected by western blotting and electrophoretic mobility shift assay(EMSA) in cultured rat VSMCs.
Results:The AT_1-AA caused a significant rat VSMC proliferation similar to the AngⅡduring 0～24 h.The term levels of NF-κB,phosphorylated JAK2 (pJAK2),phosphorylated STAT1 (pSTAT1) and phosphorylated STAT3 (pSTAT3) molecules wereincreased in response to the autoantibodies.In contrast,the activation of NF-κB andJAK-STAT was blocked by Losartan,PDTC (Pyrrolidinedithiocarbamate,a specificinhibitor of NF-κB) and AG490 (a specific inhibitor of the JAK2 tyrosine kinase)respectively.The expressions of NF-κB,the pSTAT1 and pSTAT3 reached peak levels atdifferent time stages;Moreover,the gray relative value showed that activation of pSTAT3was more significant than that of STAT1 induced by AT_1-AA.
Conclusion:These results suggest that the autoantiboies against AT_1-receptor have anagonist-like activity effect similar to AngⅡin VSMCs proliferation,and the NF-κB andJAK-STAT proteins play essential roles.Besides,it is different from AngI that STAT3 isthe main downstream activatory molecule in JAK-STAT signaling pathway.
PartⅡHLA-DRB1,-DQB1 polymorphism and autoantibodiesagainst angiotension AT_1 receptors in Chinese patients with essentialhypertension
Background and objective:The autoantibodies against angiotension AT_1 receptors(AT_1-AAs) have been discovered in patients with preeclampsia,malignant hypertensivesand essential hypertension (EH);however,the mechanism of autoantibody productionremains to be investigated.This study would analyze the association of AT_1-AAs and HLApolymorphism.
Methods:We enrolled 394 patients with EH and 224 normotensives in this study.Autoantibodies in sera of donors were detected by ELISA.The subject's clinical data wascollected,including gender,age,body mass index,blood pressure,smoking and diabetes.The patients and the controls were classified respectively into the autoantibody positive group and autoantibody negative one.DNA typing for HLA-DRB1 and HLA-DQB1 alleleswas detected by PCR amplification with sequence-specific primers.
Results:Thirteen HLA-DRB1 and seven DQB1 alleles were found in this population.We observed the differences of HLA-DRB1 and HLA-DQB1 allele frequency between EHand normotensives group.The haplotype HLA-DQB1~*06- DRB1~*13 was an independentrisk factor for EH (adjusted P=0.014,OR 3.138,95% CI 1.259-7.819) in the wholepopulation.HLA-DRB1~*04 and HLA-DRB1~*14 (respectively P=0.001,OR 3.056,95%CI1.562-5.974;P=0.033,OR 2.528,95%CI 1.080-5.914) were related to AT_1-AA productionin normotensives.HLA-DRB1~*04 was also positive related to AT_1-AA production inhypertensives after blood pressure,age and gender adjusted (P=0.07,OR 1.629,95% CI0.954-2.780).
Conclsions:These results suggest a difference in the immunogenetic backgroundbetween the positive and negative autoatibodies with hypertension or normotension.Theblood pressure and HLA-DRB1~*04 allele increased the risk for AT_1-AA production.
PartⅢAssociation about AngiotensinⅡReceptor GenePolymorphism,AT_1-receptor autoantibody production,and BloodPressure Response to Candesartan
Background:The BP response to AT_1 receptor blockers (ARBs) varied markedlyamong individuals and autoantibodies against AT_1 receptor (AT_1-AAs) were important forthe development of hypertension,our purpose was to identify the association betweenanti-AT_1-receptor autoantibody production and angiotensinⅡreceptor genes (AGTR1)polymorphism,and to study whether they were contributions to the variation in bloodpressure (BP) response to candesartan in essential hypertensive patients.
Methods:We random selected 175 essential hypertensive patients and enter an 8weeks clinical trial with candesartan treatment.We genotyped them for 3 SNPs(rs1492078,rs5186 and rs380400) in the AGTR1 genes by direct DNA sequencing. AT_1-AAs were detected by ELISA.
Results:The diastolic BP reduction response to candesartan therapy was nosignificant difference between AT_1-AA positive and negative groups.The systolic BPreduction by candesartan was greater in AT_1-AA positive groups (-35.34±17.36 mmHg)than in AT_1-AA negative ones (-28.96±14.82 mmHg),and the difference reachedstatistical significance (P=0.014,adjusted P=0.050).According to the prevalence ofAT_1-AAs,only the haplotype [GAC] was significant association with AT_1-AAs and showedthe protective effect on the AT_1-AA production (adjusted P=0.028 OR 0.342,95% CI0.131-0.890).Meanwhile,SNP rs5186 (A/C) and haplotype [GCC] were significant SBPreduction to Candesartan (adjusted P=0.028 and P=0.026,respectively),and haplotype[AAC] showed a trend toward a greater DBP reduction in response to Candesartan therapy(adjusted P=0.016).
Conclusion:AT_1-AA production might partially owe to AGTR1 gene polymorphism.Furthermore,AT_1-AAs and AGTR1 gene polymorphism could solely or jointly affectantihypertensive response to Candesartan.
背景及目的：在妊高征和恶性高血压患者血清中检测到抗血管紧张素Ⅱ1型受体自身抗体(AT_1-AA)的存在，同时有研究表明该自身抗体有类似血管紧张素Ⅱ(AngⅡ)的激动样作用并参与高血压免疫发病机制形成。在此我们将进一步阐述该自身抗体其激动样效应的细胞内信号机制。
方法：大鼠主动脉细胞培养及鉴定。同时将收集原发性高血压病人血清经硫酸铵沉淀粗提、免疫亲和层析法纯化，ELISA检测其滴度后以1：40刺激细胞，并设立不同的处理组用BrdU法观察细胞增殖情况。经western印迹方法和电泳迁移率变动分析胞内信号分子激活及表达状况。
结果：在0～24h的平滑肌细胞增殖实验中，AT_1-AA组有类似于AngⅡ的作用。Western及EMSA显示AT_1-AA组中NF-κB和磷酸化的JAK2、STAT1和STAT3水平分别较空白对照组明显增强，而表达可相应被PDTC(NF-κB拮抗剂)、AT_1受体阻滞剂Losartan和JAK2特异性拮抗剂AG490明显抑制。同时，NF-κB和磷酸化的STAT1和STAT3表达分别在不同的时间梯度达高峰，且磷酸化STAT3的活化较STAT1更为明显。
结论：高血压病人血清中AT_1-AA确有类似血管紧张素Ⅱ致平滑肌细胞增殖激动样效应，并且在该效应中伴有NF-κB、JAK-STAT信号通路的活化。且不同于AngⅡ的是，胞内JAK-STAT途径中以STAT3活化为主。
第二部分原发性高血压患者中抗AT_1受体自身抗体产生与HLA基因多态性间的关联性研究
背景及目的：在妊高征、恶性高血压和原发性高血压患者血清中都可检测到抗血管紧张素Ⅱ1型受体自身抗体(AT_1-AA)的存在，然而其产生机制至今研究的甚少。本文主要分析其与免疫基因HLA多态性间的关联。
方法：入选394例原发性高血压病人和224例正常血压健康体检者，并通过ELISA检测自身抗体滴度。我们收集入选者一般临床资料，包括性别、年龄、体重指数、血压、吸烟及糖尿病情况。高血压和正常对照组分别按抗体阴性和阳性进行分组。通过PCR序列特异性引物法(PCR-SSP)进行HLA基因分型。
结果：13种HLA-DRB1基因型和7种HLA-DQB1基因型被检测。结果表明不同的HLA-DRB1和HLA-DQB1基因型在原发性高血压和正常人群中表达频率不同，且单倍型HLA-DQB1~*06-DRB1~*13是原发性高血压形成的独立危险因素(校正后P=0．014，OR 3．138，95％CI 1．259-7．819)。正常血压者中HLA-DRB1~*04和HLA-DRB1~*14基因型与AT_1-AA产生关联(分别P=0．001，OR 3．056，95％CI 1．562-5．974；P=0．033，OR2．528，95％CI 1．080-5．914)，同时高血压患者中基因型HLA-DRB1~*04也与AT_1-AA产生相关，以P＜0．1为检验水准则其P值经校正后仍存在统计学差异(校正后P=0．07，OR 1．629，95％CI0．954-2．780)。
结论：上述结果表明高血压患者和正常人血清中自身抗体形成具有不同的免疫遗传背景，同时阐明了环境因素血压和基因易感因素HLA-DRB1~*04等位基因型与AT_1-AA产生密切相关。
第三部分抗AT_1受体自身抗体与其受体基因AGTR1多态性的关联研究、及两者对药物Candesartan降压效应的影响
背景及目的：不同的个体对降压药AT_1受体拮抗剂(ARB)的反应存在较大的差异，同时AT_1-AA在高血压的发生法发展中起到重要的作用，因此我的目的研究其降压个体差异产生的原因即降压效应与AT_1受体基因AGTR1多态性、AT_1受体自身抗体间的是否存在一定的关联性。
方法：随机选取175名原发性高血压患者进行为期8周的Candesartan临床试验，并进行AT_1-AA阳性和阴性分组。收集其血样标本进行DNA提取并通过直接测序法对AGTR1基因中三个SNP位点rs1492078、rs5186和rs380400进行分型。通过ELISA法检测AT_1-AA滴度。
结果：结果显示Candesartan治疗后抗体阳性组和阴性组间舒张压下降程度无明显差异，而收缩压的下降抗体阳性组显著多于抗体阴性组(P=0．014，校正后P=0．050)。在抗体阴阳性分组后检测到单倍型[GAC]与AT_1-AA的产生负相关(校正后P=0．028OR0．342，95％CI0．131-0．890)，而三个SNP位点中单个点基因型与其自身抗体频率间无相关性。校正了年龄、性别和自身抗体对降压药物的影响后，rs5186(A/C)和单倍型[GCC]能显著增强Candesartan降收缩压效应(校正后分别P=0．028和P=0．026)，而单倍型[AAC]则显示能增强Candesartan降舒张压效应(校正后P=0．016)。
结论：AT_1-AA的产生可能与其受体基因AGTR1存在一定的关联性。而且，AT_1-AA与AGTR1基因多态性可能独立或共同影响Candesartan的降压效应。
PartⅠThe mechanism of signal transduction in rat VSMCproliferation induced by autoantibodies against angiotensin AT_1receptor from essential hypertensives
Background and objective:The autoantibodies against angiotension AT_1 receptor(AT_1-AA) have been discovered in the patients with malignant hypertensive,preeclampsiaand essential hypertension (EH).Some studies have demonstrated the autoantiboies areinvolved in the immunopathogenesis of hypertension and have an agonist-like activityeffect similar to angiotensinⅡ(AngⅡ).We further expound the mechanism of signaltransduction induced by autoantibodies against angiotensin AT_1 receptor fromhypertensives.
Methods:The rat VSMCs were cultured and identified.The autoantiboies against AT_1receptor were purified from sera of the primary hypertension patients by ammonium sulfateprecipitation and affinity chromatography.Then the AT_1-AA collected was detected byELISA and activated cells with 1:40 and judged the effect on rat VSMC proliferation bythe method of BrdU incorporation in different treatment groups.The activation of signalingmolecules were detected by western blotting and electrophoretic mobility shift assay(EMSA) in cultured rat VSMCs.
Results:The AT_1-AA caused a significant rat VSMC proliferation similar to the AngⅡduring 0～24 h.The term levels of NF-κB,phosphorylated JAK2 (pJAK2),phosphorylated STAT1 (pSTAT1) and phosphorylated STAT3 (pSTAT3) molecules wereincreased in response to the autoantibodies.In contrast,the activation of NF-κB andJAK-STAT was blocked by Losartan,PDTC (Pyrrolidinedithiocarbamate,a specificinhibitor of NF-κB) and AG490 (a specific inhibitor of the JAK2 tyrosine kinase)respectively.The expressions of NF-κB,the pSTAT1 and pSTAT3 reached peak levels atdifferent time stages;Moreover,the gray relative value showed that activation of pSTAT3was more significant than that of STAT1 induced by AT_1-AA.
Conclusion:These results suggest that the autoantiboies against AT_1-receptor have anagonist-like activity effect similar to AngⅡin VSMCs proliferation,and the NF-κB andJAK-STAT proteins play essential roles.Besides,it is different from AngI that STAT3 isthe main downstream activatory molecule in JAK-STAT signaling pathway.
PartⅡHLA-DRB1,-DQB1 polymorphism and autoantibodiesagainst angiotension AT_1 receptors in Chinese patients with essentialhypertension
Background and objective:The autoantibodies against angiotension AT_1 receptors(AT_1-AAs) have been discovered in patients with preeclampsia,malignant hypertensivesand essential hypertension (EH);however,the mechanism of autoantibody productionremains to be investigated.This study would analyze the association of AT_1-AAs and HLApolymorphism.
Methods:We enrolled 394 patients with EH and 224 normotensives in this study.Autoantibodies in sera of donors were detected by ELISA.The subject's clinical data wascollected,including gender,age,body mass index,blood pressure,smoking and diabetes.The patients and the controls were classified respectively into the autoantibody positive group and autoantibody negative one.DNA typing for HLA-DRB1 and HLA-DQB1 alleleswas detected by PCR amplification with sequence-specific primers.
Results:Thirteen HLA-DRB1 and seven DQB1 alleles were found in this population.We observed the differences of HLA-DRB1 and HLA-DQB1 allele frequency between EHand normotensives group.The haplotype HLA-DQB1~*06- DRB1~*13 was an independentrisk factor for EH (adjusted P=0.014,OR 3.138,95% CI 1.259-7.819) in the wholepopulation.HLA-DRB1~*04 and HLA-DRB1~*14 (respectively P=0.001,OR 3.056,95%CI1.562-5.974;P=0.033,OR 2.528,95%CI 1.080-5.914) were related to AT_1-AA productionin normotensives.HLA-DRB1~*04 was also positive related to AT_1-AA production inhypertensives after blood pressure,age and gender adjusted (P=0.07,OR 1.629,95% CI0.954-2.780).
Conclsions:These results suggest a difference in the immunogenetic backgroundbetween the positive and negative autoatibodies with hypertension or normotension.Theblood pressure and HLA-DRB1~*04 allele increased the risk for AT_1-AA production.
PartⅢAssociation about AngiotensinⅡReceptor GenePolymorphism,AT_1-receptor autoantibody production,and BloodPressure Response to Candesartan
Background:The BP response to AT_1 receptor blockers (ARBs) varied markedlyamong individuals and autoantibodies against AT_1 receptor (AT_1-AAs) were important forthe development of hypertension,our purpose was to identify the association betweenanti-AT_1-receptor autoantibody production and angiotensinⅡreceptor genes (AGTR1)polymorphism,and to study whether they were contributions to the variation in bloodpressure (BP) response to candesartan in essential hypertensive patients.
Methods:We random selected 175 essential hypertensive patients and enter an 8weeks clinical trial with candesartan treatment.We genotyped them for 3 SNPs(rs1492078,rs5186 and rs380400) in the AGTR1 genes by direct DNA sequencing. AT_1-AAs were detected by ELISA.
Results:The diastolic BP reduction response to candesartan therapy was nosignificant difference between AT_1-AA positive and negative groups.The systolic BPreduction by candesartan was greater in AT_1-AA positive groups (-35.34±17.36 mmHg)than in AT_1-AA negative ones (-28.96±14.82 mmHg),and the difference reachedstatistical significance (P=0.014,adjusted P=0.050).According to the prevalence ofAT_1-AAs,only the haplotype [GAC] was significant association with AT_1-AAs and showedthe protective effect on the AT_1-AA production (adjusted P=0.028 OR 0.342,95% CI0.131-0.890).Meanwhile,SNP rs5186 (A/C) and haplotype [GCC] were significant SBPreduction to Candesartan (adjusted P=0.028 and P=0.026,respectively),and haplotype[AAC] showed a trend toward a greater DBP reduction in response to Candesartan therapy(adjusted P=0.016).
Conclusion:AT_1-AA production might partially owe to AGTR1 gene polymorphism.Furthermore,AT_1-AAs and AGTR1 gene polymorphism could solely or jointly affectantihypertensive response to Candesartan.
引文
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