Agata Jun, Chao Lee, Chao Julie
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA.
Hypertension. 2002 Nov;40(5):653-9. doi: 10.1161/01.hyp.0000036035.41122.99.
In this study, we used the somatic gene delivery approach to explore the role of the kallikrein-kinin system (KKS) in cardiac remodeling and apoptosis after myocardial infarction (MI). Rats were subjected to coronary artery ligation to induce MI, and adenovirus carrying the human tissue kallikrein or luciferase gene was injected into the tail vein at 1 week after surgery. Cardiac output gradually decreased from 2 to 6 weeks after MI, whereas delivery of the kallikrein gene prevented this decrease. Cardiac responses to dobutamine-induced stress were improved in rats receiving kallikrein gene as compared with rats receiving control virus at 6 weeks after MI. Kallikrein significantly improved cardiac remodeling by decreasing collagen density, cardiomyocyte size, and left ventricular internal perimeter and increasing capillary density in the heart at 6 weeks after MI. Kallikrein gene transfer attenuated myocardial apoptosis, which was positively correlated with remodeling parameters in the heart at 2 weeks after MI. Endothelial dysfunction, characterized by increased vascular resistance, decreased left ventricular blood flow, and decreased cardiac nitric oxide levels, existed in remodeled hearts at 2 weeks after MI, whereas kallikrein gene transfer improved these parameters. Kallikrein gene delivery improved cell survival parameters as shown by increased phospho-Akt and reduced caspase-3 activation at 2 weeks after MI. This study indicates that the kallikrein-kinin system plays an important role in preventing the progression of heart failure by attenuating cardiac hypertrophy and fibrosis, improving endothelial function, and inhibiting myocardial apoptosis through the Akt-mediated signaling pathway.
在本研究中，我们采用体细胞基因递送方法来探究激肽释放酶-激肽系统（KKS）在心肌梗死（MI）后心脏重塑和细胞凋亡中的作用。对大鼠进行冠状动脉结扎以诱导MI，并在术后1周将携带人组织激肽释放酶或荧光素酶基因的腺病毒注入尾静脉。MI后2至6周心输出量逐渐下降，而激肽释放酶基因的递送可防止这种下降。与MI后6周接受对照病毒的大鼠相比，接受激肽释放酶基因的大鼠对多巴酚丁胺诱导的应激的心脏反应得到改善。MI后6周，激肽释放酶通过降低胶原密度、心肌细胞大小和左心室内周长并增加心脏毛细血管密度，显著改善了心脏重塑。激肽释放酶基因转移减轻了心肌细胞凋亡，这与MI后2周心脏中的重塑参数呈正相关。MI后2周，重塑心脏中存在内皮功能障碍，其特征为血管阻力增加、左心室血流量减少和心脏一氧化氮水平降低，而激肽释放酶基因转移改善了这些参数。MI后2周，激肽释放酶基因递送改善了细胞存活参数，表现为磷酸化Akt增加和半胱天冬酶-3激活减少。本研究表明，激肽释放酶-激肽系统通过减轻心脏肥大和纤维化、改善内皮功能以及通过Akt介导的信号通路抑制心肌细胞凋亡，在预防心力衰竭进展中发挥重要作用。
