Cardiac function and remodeling is attenuated in transgenic rats expressing the human kallikrein-1 gene after myocardial infarction
Cardiac function and remodeling is attenuated in transgenic rats expressing the human kallikrein-1 gene after myocardial infarction
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DOI：
10.1016/j.ejphar.2006.08.054
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发表时间：
2006-11-21
影响因子：
5
通讯作者：
Tschoepe, Carsten
中科院分区：
文献类型：
--
作者：
Koch, Matthias;Spillmann, Frank;Tschoepe, Carsten
在基础和缺血条件下研究了携带人组织激肽释放酶-1基因TGR（hKLK1）的转基因大鼠的缓激肽冠状动脉流出物、左心室性能和左心室尺寸。在全缺血前后，通过特异性放射免疫测定法测量了灌注缓冲液的对照离体心脏和TGR（bKLK1）冠状动脉流出物中缓激肽的含量。在诱导心肌梗塞后6天和3周，使用尖端导管和超声心动图在体内测定左心室功能和左心室尺寸。通过 RNase 保护测定分析左心室 I 型胶原 mRNA 表达。与对照组相比，TGR（hKLK1）的基础缓激肽流出量增加了 3.5 倍。缺血导致对照组缓激肽冠状动脉流出量增加，但没有诱导 TGR（hKLK1）进一步增加。然而，尽管梗塞面积相似，但心肌梗塞后 TGR(hKLK1) 的左心室功能和重构有所改善，表现为左心室压力增加 (+34%；P < 0.05)、收缩力增加 (dp/dt max. +25%；P < 0.05)、射血分数增加 (+20%；P < 0.05) 以及左心室舒张末压降低。与对照组相比，左心室舒张末期内径（-49%，P < 0.05）、左心室舒张末期内径（-20%，P < 0.05）和胶原 mRNA 表达（-15%，P < 0.05）。 表达人激肽释放酶-1 基因的长期激活的转基因激肽释放酶激肽系统可抵消实验性心肌梗死后左心室收缩功能障碍的进展。进一步的研究必须表明这些结果是否可能是由其他治疗选择引起的。长效缓激肽受体激动剂可能是改善缺血性心脏病的另一种选择。 (c) 2006 Elsevier B.V. 保留所有权利。
Bradykinin coronary outflow, left ventricular performance and left ventricular dimensions of transgenic rats harboring the human tissue kallikrein-1 gene TGR(hKLK1) were investigated under basal and ischemic conditions.Bradykinin content in the coronary outflow of buffer-perfused, isolated hearts of controls and TGR(bKLK1) was measured by specific radioimmunoassay before and after global ischemia. Left ventricular function and left ventricular dimensions were determined in vivo using a tip catheter and echocardiography 6 days and 3 weeks after induction of myocardial infarction. Left ventricular type I collagen mRNA expression was analyzed by RNase protection assay. Compared to controls, basal bradykinin outflow was 3.5 fold increased in TGR(hKLK1). Ischemia induced an increase of bradykinin coronary outflow in controls but did not induce a further increase in TGR(hKLK1). However, despite similar unchanged infarction sizes, left ventricular function and remodeling improved in TGR(hKLK1) after myocardial infarction, indicated by an increase in left ventricular pressure (+34%; P < 0.05), contractility (dp/dt max. +25%; P < 0.05), and in ejection fraction (+20%; P < 0.05) as well as by a reduction in left ventricular enddiastolic pressure (-49%, P < 0.05), left ventricular enddiastolic diameter (-20%, P < 0.05), and collagen mRNA expression (-15%, P < 0.05) compared to controls.A chronically activated transgenic kallikrein kinin system with expression of human kallikrein-1 gene counteracts the progression of left ventricular contractile dysfunction after experimental myocardial infarction. Further studies have to show whether these results can be caused by other therapeutically options. Long acting bradykinin receptor agonists might be an alternative option to improve ischemic heart disease. (c) 2006 Elsevier B.V. All rights reserved.