Evidence for involvement of calcitonin gene-related peptide in nitroglycerin response and association with mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism
Evidence for involvement of calcitonin gene-related peptide in nitroglycerin response and association with mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism
复制标题
降钙素基因相关肽参与硝酸甘油反应以及与线粒体醛脱氢酶 2 (ALDH2) Glu504Lys 多态性相关的证据
DOI：
10.1016/j.jacc.2008.05.049
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发表时间：
2008-09-09
影响因子：
24
通讯作者：
Li, Yuan-Jian
中科院分区：
文献类型：
--
作者：
Guo, Ren;Chen, Xiao-Ping;Li, Yuan-Jian
目的探讨降钙素基因相关肽（calcitonin gene-related peptide，CGRP）是否参与了硝酸甘油（glyceryl trinitrate，GTN）的心血管效应及其与线粒体乙醛脱氢酶2（aldehyde dehydrogenase-2，ALDH 2）Glu504Lys（ALDH 2 * 2）基因多态性的关系。主要负责GTN生物活化的酶是ALDH 2。方法对18名ALDH2 * 2基因型正常的中国志愿者，观察舌下含服GTN后血浆CGRP浓度的变化及其与GTN疗效的相关性，用10（-5）mol/L的地塞米松预处理培养的外周血单个核细胞（PBMC），检测CGRP信使核糖核酸（mRNA）的表达。结果与ALDH 2 * 2等位基因携带者相比，ALDH 2 * 1/* 1纯合子在GTN给药后的几个时间点的收缩压（Δ SBP）和心率（Δ HR）的绝对变化幅度显著更大。GTN给药后12 min血浆CGRP浓度显著升高，血浆CGRP浓度升高百分比与Δ SBP和Δ HR均呈正相关，ALDH 2 * 1/* 1纯合子血浆CGRP浓度升高百分比显著较高。此外，从ALDH2 * 1/* 1纯合子PBMCs显示了更高的倍数增加CGRP I和CGRP II mRNA GTN刺激后，和GTN诱导的增加CGRP mRNA表达的ALDH2抑制剂水合氯醛从ALDH2 * 1/* 1纯合子PBMCs的抑制。结论我们发现，CGRP是通过ALDH2依赖性途径与GTN的心血管效应在人类。
Objectives This study sought to determine whether calcitonin gene-related peptide (CGRP) is involved in glyceryl trinitrate (GTN) response in humans, and its association with mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys (ALDH2*2) polymorphism.Background In animal models, CGRP contributes to the cardiovascular effects of GTN. The enzyme principally responsible for GTN bioactivation is ALDH2. The common ALDH2*2 polymorphism is associated with a lack of GTN efficacy.Methods In 18 ALDH2*2-genotyped Chinese volunteers, we observed the changes in plasma concentrations of CGRP after sublingual GTN administration and its correlation with GTN response, and assessed the expression of CGRP messenger ribonucleic acid (mRNA) in cultured peripheral blood mononuclear cells (PBMCs) pre-treated with 10(-5) mol/l GTN.Results In contrast to carriers of the ALDH2*2 allele, ALDH2*1/*1 homozygotes showed a significantly higher extent of absolute changes in both systolic blood pressure (Delta SBP) and HR (Delta HR) at several time points after GTN administration. Plasma concentrations of CGRP were increased significantly 12 min after GTN administration, the percentage increase in plasma concentrations of CGRP correlated positively with both Delta SBP and Delta HR, and percentage increase in plasma concentrations of CGRP was significantly higher in ALDH2*1/*1 homozygotes. In addition, PBMCs from ALDH2*1/*1 homozygotes showed a higher-fold increase in both CGRP I and CGRP II mRNA after GTN stimulation, and the GTN-induced increase in CGRP mRNA expression in PBMCs from ALDH2*1/*1 homozygotes was inhibited by the ALDH2 inhibitor chloral hydrate.Conclusions We found that CGRP is associated with the cardiovascular effect of GTN through an ALDH2-dependent pathway in humans.