Transgenic A(1) adenosine receptor overexpression increases myocardial resistance to ischemia
Transgenic A(1) adenosine receptor overexpression increases myocardial resistance to ischemia
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DOI：
10.1073/pnas.94.12.6541
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发表时间：
1997-06-10
影响因子：
11.1
通讯作者：
Headrick, JP
中科院分区：
文献类型：
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作者：
Matherne, GP;Linden, J;Headrick, JP
心肌A(1)腺苷受体(A(1)AR)的激活保护心脏免受缺血损伤，在本研究中，使用心脏特异的α-肌球蛋白重链启动子和大鼠A(1)AR基因建立了转基因小鼠。来自两个转基因阳性细胞系的心脏膜显示A(1)AR的过度表达接近1,000倍(6,574+/-965和10,691+/-1,002fmol/mg蛋白vs，8+/-5fmol/mg蛋白在对照心脏中)，与对照心脏相比，转基因兰登多夫灌流心脏的固有心率显著降低(248次/分钟vs，318次/min，P<；0.05)，较低的发展张力(1.2g vs，1.6g，P<；用50 mU M 8-(对磺基苯基)茶碱阻断腺苷受体，但不受A(1)AR激动剂20 nM N-6-环戊基腺苷的影响。因此，A(1)缺血心肌AR可能被内源性腺苷饱和，过表达心肌A(1)AR可延长缺血收缩时间并促进再灌注期的功能恢复。但这种反应受小鼠心肌A(1)AR数目的限制。A(1)AR的过度表达提供了额外的保护，这些数据支持基因操作A(1)AR表达可能改善心肌对缺血的耐受性的概念。
Activation of myocardial A(1) adenosine receptors (A(1)AR) protects the heart from ischemic injury, In this study transgenic mice were created using the cardiac-specific alpha-myosin heavy chain promoter and rat A(1)AR cDNA. Heart membranes from two transgene positive lines displayed approximate to 1,000-fold overexpression of A(1)AR (6,574 +/- 965 and 10,691 +/- 1,002 fmol per mg of protein vs, 8 +/- 5 fmol per mg of protein in control hearts), Compared with control hearts, transgenic Langendorff-perfused hearts had a significantly lower intrinsic heart rate (248 beats per min vs, 318 beats per min, P < 0.05), lower developed tension (1.2 g vs, 1.6 g, P < 0.05), and similar coronary resistance, The difference in developed tension was eliminated by pacing, Injury of control hearts during global ischemia, indexed by time-to-ischemic contracture, was accelerated by blocking adenosine receptors with 50 mu M 8-(p-sulfophenyl) theophylline but was unaffected by addition of 20 nM N-6-cyclopentyladenosine, an A(1)AR agonist, Thus A(1)ARs in ischemic myocardium are presumably saturated by endogenous adenosine, Overexpressing myocardial A(1)ARs increased time-to-ischemic contracture and improved functional recovery during reperfusion, The data indicate that A(1)AR activation by endogenous adenosine affords protection during ischemia, but that the response is limited by A(1)AR number in murine myocardium. Overexpression of A(1)AR affords additional protection, These data support the concept that genetic manipulation of A(1)AR expression may improve myocardial tolerance to ischemia.