冠心病患者血小板miR-223和miR-96差异表达与氯吡格雷反应性的关联研究
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摘要
研究目的：目前大量临床及实验研究显示“抗血小板药物抵抗”主要与血小板反应活性存在个体差异有关,因此需要对服用抗血小板药物的患者进行血小板反应活性的监测。但临床上对于血小板反应活性判定的各种实验诊断标准尚未达成一致。微小RNA (microRNA, miRNA)是一类在进化上高度保守的单链非编码小RNA,新近研究表明人血小板中含有miRNA,其表达谱差异与血小板功能密切相关,由此可影响疾病的易感性,特别是血小板反应活性的差异。因此本研究的目的是探讨冠心病患者血小板microRNA(miR-223, miR-96)表达水平与氯吡格雷反应性的关系,为抗血小板药物个体反应的差异性提供新的分子水平机制及人群研究证据。
研究内容与方法：以不稳定型心绞痛(Unstable Angina Pectoris, UAP)患者为研究对象。记录患者的一般临床资料及用药情况；进行各项血细胞参数、生化参数的检验；进行心脏超声、踝-臂指数及臂踝脉搏波传导速度的检查；进行冠脉造影检查及必要的介入治疗。对冠脉病变进行Gensini评分及Syntax评分。以二磷酸腺苷(Adenosine Diphosphate, ADP)诱导的血小板聚集率和通过流式细胞术测定的血小板血管舒张剂刺激磷蛋白(Vasodilator Stimulated Phosphoprotein, VASP)磷酸化水平,判断患者在服用氯吡格雷后血小板反应活性的情况。以CD45免疫磁珠去除富血小板血浆中残留的白细胞后,提取患者血小板中的miRNA,对与血小板P2Y12受体mRNA3'非编码区结合的miR-223,及与血小板小泡缔合性微管蛋白8(Vesicle-Associated Microtubule Protein8, VAMP8)表达调节相关的miR-96的表达进行实时定量聚合酶链反应(Real Time Polymerase Chain Reaction, real time PCR)分析。
结果：①所有入选患者根据流式细胞术测定的VASP磷酸化水平即血小板反应指数(Platelet Reactivity Index, PRI)的中位数水平(56.55%)分成2组：A组<56.55%,18例,男9例,女9例；B组>55.66%,18例,男7例,女11例。②两组患者的年龄、性别构成、体重指数及药物使用情况无统计学差异(P>0.05)。两组患者的心血管疾病史、伴发疾病情况及入院时的血压、心率无统计学差异(P>0.05)。两组患者的心脏功能及结构、ABI、BaPWV、各项血细胞参数及生化参数均无统计学差异(P>0.05)。血小板聚集率两组间有统计学差异(36.64±15.24vs52.19±13.17,P=0.002)。③两组患者TIMI分级、Syntax评分及Gensim评分无统计学差异(P>0.05)。支架长度两组间有统计学差异(28.22±19.65vs12.39±15.47,P=0.011)。④PRI与血小板聚集率呈正相关(r=0.400,P=0.016)。支架长度与Syntax评分呈正相关(r=0.457,P=0.005)。支架长度与Gensim评分呈正相关(r=0.497,P=0.002)。Syntax评分与Gensim评分呈正相关(r=0.660,P=0.000)。⑤与A组比较,B组miR-223相对表达水平下调,有统计学差异(P=0.0398)；B组miR-96相对表达水平有下调的趋势,但无统计学差异(P=0.073)。⑥miR-223相对表达水平与血小板聚集率间无相关性(r=0.0339,P=0.8513),与PRI呈负相关(r=-0.4045,P=0.0328)；miR-96相对表达水平与血小板聚集率间无相关性(r=0.1473,P=0.4546),与PRI无相关性(r=-0.0186,P=0.9251)
结论：本研究入选患者在服用双联抗血小板治疗后,血小板反应活性存在明显的个体差异,通过光比浊法检测的血小板聚集率与流式细胞术检测的VASP磷酸化程度的两种方法均可对治疗后血小板反应活性进行评估,两者具有一定的相关性。可将两种评估方法结合在一起评价冠心病患者抗血小板治疗后血小板的反应活性。本研究中冠心病患者血小板miR-223的低表达与血小板高反应性之间存在联系,为抗血小板药物个体差异性提供了新的分子水平机制及人群研究证据。
Objectives:Currently, a large number of clinical trials and basic researches ascribed "anti-platelet drug resistance" to interindividual variation in platelet reactivity. Therefore it is necessary to monitor the platelet reactivity of patients who are taking anti-platelet drugs. However in clinical practice, the methods for determining the reactivity of platelet do not have a regular standard. MicroRNA (miRNA) is a class of non-coding RNA whose final product is a～22nt functional RNA molecule. Recent data indicated that human platelets contain miRNA, and their expression profile is closely related to platelet reactivity. Meanwhile this variance in miRNA expression profile could impact diseases'susceptibility, especially the heterogenicity of platelet reactivity. Therefore, the purpose of the present work is to investigate the relationship between platelet miRNA (miR-223, miR-96) expression and clopidogrel response in paticnts with coronary artery disease, which could provide novel molecular mechanism underlying inter-individual variability of platelet reactivity.
Materials and Methods:Thirty-six patients with unstable angina pectoris were enrolled in the study. Main demographic and clinical characteristics of the study population were recorded. Patients'blood cell parameters and bio-chemical parameters were tested. We performed cardiac ultrasound, ankle-brachial index and brachial-ankle artery pulse wave velocity measurement to all patients. And all patients underwent coronary artery angiography (CAG) and received appropriate coronary artery interventional treatment. Gensini score and Syntax score were calculated according to quantitative CAG. Platelet reactivity after loading doses of clopidogrel was assessed with10μmol/L adenosine diphosphate (ADP)-induced light transmittance aggregometry and with vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay by flow cytometric analysis.
Because platelet preparations are often contaminated by leukocytes, and small amounts of residual leukocytes, which have much higher levels of RNA than platelets, may cause false detection of miRNA. We therefore carried out leukocyte depletion with anti-CD45conjugated magnetic beads according to the manufacturer's recommendations. Then we extracted miRNA in platelet. The expression analysis of miRNA-223which is band to3'UTR of platelet P2Y12receptor and miR-96which is related to platelet vesicle-associated microtubule protein8(VAMP8) expression regulation was performed using real time Polymerase Chain Reaction (real time PCR).
Results:①All patients were divided into2groups by platelet reactivity index (PRI) median level (56.55%) which was assessed with VASP phosphorylation assay by flow cytometric analysis. Group A with PRI<56.55%, consisted of9male and9female. Group B with PRI>56.55%, consisted of7male,11female.②There was no statistical differences (P>0.05) in age, gender, body mass index and medications between two groups. There was no between-group statistical differences (P>0.05) in cardiovascular disease history, complications, blood pressure and heart rate when they were admitted to hospital. There was no statistical differences (P>0.05) interms of cardiac function, ABI, BaPWV, blood cell parameters and bio-chemical parameters. There was statistical differences (36.64±15.24vs52.19±13.17, P=0.002) in platelet aggregation rate between two groups.③There was no statistical differences (P>0.05) in TIMI grading, Syntax score and Gensim score. There is statistical differences (28.22±19.65vs12.39±15.47, P=0.011) in stents'length between two groups.④There was a positive correlation between PRI and platelet (r=0.400, P=0.016). There was a positive correlation between stents'length and Syntax score(r=0.457,P=0.005). There was a positive correlation between stents'length and Genism score (r=0.497, P=0.002). There was a positive correlation between Syntax score and Genism score (r=0.660,P=0.000).⑤Compared with A group, the relative expression of miR-223was down regulated with statistical differences (P=0.0398), while the expression of miR-96presented with down-regulated trend, no statistical difference was observed (P=0.073).⑥There was a negative correlation between the relative expression quantity of miR-223and PRI (r=-0.4045, P=0.0328). There was no correlation between the relative expression quantity of miR-96and PRI (r=-0.0186, P=0.9251)
Conclusions:The present work for the first time demonstrated that heterogenicity of human platelet response to clopidogrel is correlated with expression pattern of platelet microRNA. Sepcifially, down-regulation of miR-223is associated with a blunted response to clopidogrel (increased platelet reactivity index measured by VASP phosphorylation) in CHD patients. Our results may provide novel molecular mechanism underlying inter-individual response to anti-platetlet drugs, and would be helpful for individualized drug dosing in clinical practice.
研究内容与方法：以不稳定型心绞痛(Unstable Angina Pectoris, UAP)患者为研究对象。记录患者的一般临床资料及用药情况；进行各项血细胞参数、生化参数的检验；进行心脏超声、踝-臂指数及臂踝脉搏波传导速度的检查；进行冠脉造影检查及必要的介入治疗。对冠脉病变进行Gensini评分及Syntax评分。以二磷酸腺苷(Adenosine Diphosphate, ADP)诱导的血小板聚集率和通过流式细胞术测定的血小板血管舒张剂刺激磷蛋白(Vasodilator Stimulated Phosphoprotein, VASP)磷酸化水平,判断患者在服用氯吡格雷后血小板反应活性的情况。以CD45免疫磁珠去除富血小板血浆中残留的白细胞后,提取患者血小板中的miRNA,对与血小板P2Y12受体mRNA3'非编码区结合的miR-223,及与血小板小泡缔合性微管蛋白8(Vesicle-Associated Microtubule Protein8, VAMP8)表达调节相关的miR-96的表达进行实时定量聚合酶链反应(Real Time Polymerase Chain Reaction, real time PCR)分析。
结果：①所有入选患者根据流式细胞术测定的VASP磷酸化水平即血小板反应指数(Platelet Reactivity Index, PRI)的中位数水平(56.55%)分成2组：A组<56.55%,18例,男9例,女9例；B组>55.66%,18例,男7例,女11例。②两组患者的年龄、性别构成、体重指数及药物使用情况无统计学差异(P>0.05)。两组患者的心血管疾病史、伴发疾病情况及入院时的血压、心率无统计学差异(P>0.05)。两组患者的心脏功能及结构、ABI、BaPWV、各项血细胞参数及生化参数均无统计学差异(P>0.05)。血小板聚集率两组间有统计学差异(36.64±15.24vs52.19±13.17,P=0.002)。③两组患者TIMI分级、Syntax评分及Gensim评分无统计学差异(P>0.05)。支架长度两组间有统计学差异(28.22±19.65vs12.39±15.47,P=0.011)。④PRI与血小板聚集率呈正相关(r=0.400,P=0.016)。支架长度与Syntax评分呈正相关(r=0.457,P=0.005)。支架长度与Gensim评分呈正相关(r=0.497,P=0.002)。Syntax评分与Gensim评分呈正相关(r=0.660,P=0.000)。⑤与A组比较,B组miR-223相对表达水平下调,有统计学差异(P=0.0398)；B组miR-96相对表达水平有下调的趋势,但无统计学差异(P=0.073)。⑥miR-223相对表达水平与血小板聚集率间无相关性(r=0.0339,P=0.8513),与PRI呈负相关(r=-0.4045,P=0.0328)；miR-96相对表达水平与血小板聚集率间无相关性(r=0.1473,P=0.4546),与PRI无相关性(r=-0.0186,P=0.9251)
结论：本研究入选患者在服用双联抗血小板治疗后,血小板反应活性存在明显的个体差异,通过光比浊法检测的血小板聚集率与流式细胞术检测的VASP磷酸化程度的两种方法均可对治疗后血小板反应活性进行评估,两者具有一定的相关性。可将两种评估方法结合在一起评价冠心病患者抗血小板治疗后血小板的反应活性。本研究中冠心病患者血小板miR-223的低表达与血小板高反应性之间存在联系,为抗血小板药物个体差异性提供了新的分子水平机制及人群研究证据。
Objectives:Currently, a large number of clinical trials and basic researches ascribed "anti-platelet drug resistance" to interindividual variation in platelet reactivity. Therefore it is necessary to monitor the platelet reactivity of patients who are taking anti-platelet drugs. However in clinical practice, the methods for determining the reactivity of platelet do not have a regular standard. MicroRNA (miRNA) is a class of non-coding RNA whose final product is a～22nt functional RNA molecule. Recent data indicated that human platelets contain miRNA, and their expression profile is closely related to platelet reactivity. Meanwhile this variance in miRNA expression profile could impact diseases'susceptibility, especially the heterogenicity of platelet reactivity. Therefore, the purpose of the present work is to investigate the relationship between platelet miRNA (miR-223, miR-96) expression and clopidogrel response in paticnts with coronary artery disease, which could provide novel molecular mechanism underlying inter-individual variability of platelet reactivity.
Materials and Methods:Thirty-six patients with unstable angina pectoris were enrolled in the study. Main demographic and clinical characteristics of the study population were recorded. Patients'blood cell parameters and bio-chemical parameters were tested. We performed cardiac ultrasound, ankle-brachial index and brachial-ankle artery pulse wave velocity measurement to all patients. And all patients underwent coronary artery angiography (CAG) and received appropriate coronary artery interventional treatment. Gensini score and Syntax score were calculated according to quantitative CAG. Platelet reactivity after loading doses of clopidogrel was assessed with10μmol/L adenosine diphosphate (ADP)-induced light transmittance aggregometry and with vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay by flow cytometric analysis.
Because platelet preparations are often contaminated by leukocytes, and small amounts of residual leukocytes, which have much higher levels of RNA than platelets, may cause false detection of miRNA. We therefore carried out leukocyte depletion with anti-CD45conjugated magnetic beads according to the manufacturer's recommendations. Then we extracted miRNA in platelet. The expression analysis of miRNA-223which is band to3'UTR of platelet P2Y12receptor and miR-96which is related to platelet vesicle-associated microtubule protein8(VAMP8) expression regulation was performed using real time Polymerase Chain Reaction (real time PCR).
Results:①All patients were divided into2groups by platelet reactivity index (PRI) median level (56.55%) which was assessed with VASP phosphorylation assay by flow cytometric analysis. Group A with PRI<56.55%, consisted of9male and9female. Group B with PRI>56.55%, consisted of7male,11female.②There was no statistical differences (P>0.05) in age, gender, body mass index and medications between two groups. There was no between-group statistical differences (P>0.05) in cardiovascular disease history, complications, blood pressure and heart rate when they were admitted to hospital. There was no statistical differences (P>0.05) interms of cardiac function, ABI, BaPWV, blood cell parameters and bio-chemical parameters. There was statistical differences (36.64±15.24vs52.19±13.17, P=0.002) in platelet aggregation rate between two groups.③There was no statistical differences (P>0.05) in TIMI grading, Syntax score and Gensim score. There is statistical differences (28.22±19.65vs12.39±15.47, P=0.011) in stents'length between two groups.④There was a positive correlation between PRI and platelet (r=0.400, P=0.016). There was a positive correlation between stents'length and Syntax score(r=0.457,P=0.005). There was a positive correlation between stents'length and Genism score (r=0.497, P=0.002). There was a positive correlation between Syntax score and Genism score (r=0.660,P=0.000).⑤Compared with A group, the relative expression of miR-223was down regulated with statistical differences (P=0.0398), while the expression of miR-96presented with down-regulated trend, no statistical difference was observed (P=0.073).⑥There was a negative correlation between the relative expression quantity of miR-223and PRI (r=-0.4045, P=0.0328). There was no correlation between the relative expression quantity of miR-96and PRI (r=-0.0186, P=0.9251)
Conclusions:The present work for the first time demonstrated that heterogenicity of human platelet response to clopidogrel is correlated with expression pattern of platelet microRNA. Sepcifially, down-regulation of miR-223is associated with a blunted response to clopidogrel (increased platelet reactivity index measured by VASP phosphorylation) in CHD patients. Our results may provide novel molecular mechanism underlying inter-individual response to anti-platetlet drugs, and would be helpful for individualized drug dosing in clinical practice.
引文
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