Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury
Deletion of the mouse α-calcitonin gene-related peptide gene increases the vulnerability of the heart to ischemia-reperfusion injury
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DOI：
10.1152/ajpheart.00749.2007
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发表时间：
2008-03-01
影响因子：
4.8
通讯作者：
Abela, George S.
中科院分区：
文献类型：
--
作者：
Huang, Ruiping;Karve, Amrita;Abela, George S.
降钙素基因相关肽（CGRP）是辣椒素敏感的c -纤维和a- delta纤维感觉神经释放的一种有效的血管扩张剂，被认为在心肌缺血再灌注（I/R）损伤中起有益作用。由于以往显示CGRP具有心脏保护作用的研究大多采用药理学实验，因此本研究的目的是利用遗传学方法，通过靶向缺失α -CGRP基因的小鼠来确定该神经肽是否对I/R损伤的严重程度具有调节功能。为了实现这一目标，将α - cgrp敲除（KO）小鼠和野生型（WT）小鼠分离的灌注心脏进行30分钟缺血，然后进行5、15和30分钟的再灌注。在I/R损伤前后测量心脏功能参数，包括冠状动脉流速、左心室发展压、最大压力发展率和左心室舒张末期压，以及评估心肌损伤的肌酸激酶水平和评估氧化应激的丙二醛水平。I/R损伤后，与WT小鼠相比，α - cgrp KO小鼠的心脏功能显著降低。I/R损伤后，与WT心脏相比，α - cgrp KO心脏心肌功能的显著下降与心肌组织中肌酸激酶向灌注液释放和丙二醛生成的显著升高有关。因此，这些数据表明，在体外环境下，α - cgrp的缺失使心脏更容易受到I/R损伤，这可能至少部分是由于氧化应激增加。
Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive C-fiber and A delta-fiber sensory nerves, has been suggested to play a beneficial role in myocardial ischemia-reperfusion (I/R) injury. Because most previous studies showing a cardioprotective role of CGRP employed pharmacological experiments, the purpose of this study was to utilize a genetic approach by using mice with a targeted deletion of the alpha-CGRP gene to determine whether this neuropeptide had a modulatory function on the severity of I/R injury. To accomplish this goal, isolated, perfused hearts from alpha-CGRP knockout (KO) and wild-type (WT) mice were subjected to 30 min of ischemia followed by 5, 15, and 30 min of reperfusion. Cardiac functional parameters, including coronary flow rates, left ventricular developed pressure, maximum rates of pressure development, and left ventricular end-diastolic pressure, were measured before and after I/R injury, as were levels of creatine kinase, to assess myocardial damage, and malonaldehyde, to assess oxidative stress. Following I/R injury, cardiac performance was significantly reduced in the hearts from the alpha-CGRP KO mice compared with their WT counterparts. The markedreduction in myocardial function in the alpha-CGRP KO hearts compared with WT hearts after I/R injury was associated with a significant elevation in creatine kinase release into the perfusates and malonaldehyde production in the cardiac tissue. Therefore, these data indicate that, in this in vitro setting, deletion of alpha-CGRP makes the heart more vulnerable to I/R injury, possibly due, at least in part, to increased oxidative stress.