Angiotensin-converting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin.
Angiotensin-converting enzyme insertion/deletion polymorphism modulates the human in vivo metabolism of bradykinin.
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DOI：
10.1161/01.cir.102.8.829
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发表时间：
2000-08
期刊：
影响因子：
37.8
通讯作者：
L. Murphey;J. Gainer;D. Vaughan;N. Brown
中科院分区：
文献类型：
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作者：
L. Murphey;J. Gainer;D. Vaughan;N. Brown
背景缓激肽是一种由血管紧张素转换酶（ACE）代谢的心脏保护肽。ACE基因的插入/缺失（I/D）多态性决定血浆ACE水平。D等位基因与心血管疾病相关，这可能与血管紧张素II产生增加或缓激肽降解为无活性代谢物缓激肽1-5（BK 1 -5）增加有关。因此，我们确定了ACE I/D多态性对人体缓激肽代谢的影响。方法和结果将缓激肽（400 ng/min）注入ACE I/I、I/D或D/D基因型志愿者（各n=9）的肱动脉。采用液相色谱-质谱联用技术定量测定前臂静脉回流中的缓激肽和BK 1 -5水平。D/D基因型患者血浆ACE活性最高（36.8+/-6.2 U/mL），I/D基因型患者居中（25.3+/-3.3 U/mL），I/I基因型患者最低（20.3+/-2.3 U/mL; D等位基因数量的影响P=0.017）。I/I、I/D和D/D受试者的缓激肽浓度分别为726+/-242，469 +/-50，545 +/-104 fmol/mL（P>0. 05）。10）。D等位基因数量与BK 1 -5浓度（I/I、I/D和D/D组分别为1113+/-290，1520+/-318和1887+/-388 fmol/mL; P=0.027）以及BK 1 -5与缓激肽的比值（1.87+/-0.35，3.09 +/-0.35）之间存在显著相关性。I/I、I/D和D/D志愿者分别为4.31+/-0.97; P=0.010）。静脉血BK 1 -5：缓激肽比值与血浆ACE活性相关（r（2）=0.16，P=0.039），总激肽浓度与前臂净组织纤溶酶原激活物释放相关（r（2）=0.20，P=0.027）。结论ACE D等位基因对缓激肽在人体内的降解有显著影响。BK_（1 -5）：缓激肽比值可作为组织ACE活性的一个指标。
BACKGROUND Bradykinin is a cardioprotective peptide metabolized by the angiotensin-converting enzyme (ACE). An insertion/deletion (I/D) polymorphism in the ACE gene determines plasma ACE levels. The D allele is associated with cardiovascular disease, which may relate to enhanced angiotensin II production or to increased bradykinin degradation to the inactive metabolite bradykinin 1-5 (BK1-5). Therefore, we determined the effect of the ACE I/D polymorphism on human bradykinin metabolism in vivo. METHODS AND RESULTS Bradykinin (400 ng/min) was infused into the brachial artery of volunteers with ACE I/I, I/D, or D/D genotypes (n=9 each). The bradykinin and BK1-5 levels in forearm venous return were quantified by liquid chromatography-mass spectroscopy. Plasma ACE activity was highest in those with the D/D genotype (36.8+/-6.2 U/mL), intermediate in those with the I/D genotype (25.3+/-3.3 U/mL), and lowest in those with the I/I genotype (20.3+/-2.3 U/mL; P=0.017 for effect of number of D alleles). Bradykinin concentrations were 726+/-242, 469+/-50, and 545+/-104 fmol/mL in I/I, I/D, and D/D subjects, respectively (P>0. 10). Significant correlations existed between the number of D alleles and BK1-5 concentrations (1113+/-290, 1520+/-318, and 1887+/-388 fmol/mL in the I/I, I/D, and D/D groups, respectively; P=0.027) and the ratio of BK1-5 to bradykinin (1.87+/-0.35, 3.09+/-0. 40, and 4.31+/-0.97 in the I/I, I/D, and D/D volunteers, respectively; P=0.010). The venous blood BK1-5:bradykinin ratio correlated with plasma ACE activity (r(2)=0.16, P=0.039), and total kinin concentration correlated with net tissue plasminogen activator release across the forearm (r(2)=0.20, P=0.027). CONCLUSIONS The ACE D allele has a significant effect on the in vivo degradation of bradykinin in humans. The ratio of BK1-5:bradykinin may serve as a marker for tissue ACE activity.