Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats
Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats
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DOI：
10.1152/ajpheart.01129.2002
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发表时间：
2003-10-01
影响因子：
4.8
通讯作者：
Chao, J
中科院分区：
文献类型：
--
作者：
Bledsoe, G;Chao, L;Chao, J
导致左心室（LV）肥大和/或纤维化的高血压可导致心功能障碍。自发性高血压大鼠（SHR）在幼年时发生高血压和LV肥大，是人类原发性高血压的流行模型。为了研究组织激肽释放酶-激肽系统在心脏重塑中的作用，将含有人组织激肽释放酶基因的腺病毒静脉注射到成年SHR和血压正常的Wistar-Kyoto（WKY）大鼠中。WKY大鼠的血压在整个实验过程中保持不变。另外，激肽释放酶基因转移降低血压在SHR的第一个2周，但从3至5周没有效果。在激肽释放酶基因递送后5周，SHR表现出左心室-心脏重量比、左心室长轴和心肌细胞大小的显著降低;然而，WKY大鼠的这些参数不受影响。有趣的是，心脏胶原密度在接受激肽释放酶基因的SHR和WKY大鼠中均降低。激肽释放酶基因转移也增加了SHR的心脏毛细血管密度，但在WKY大鼠中没有。激肽释放酶基因转移后的形态学变化与JNK活化以及心脏中转化生长因子（TGF）-β 1和纤溶酶原激活物抑制剂-1水平的降低相关。此外，激肽释放酶基因传递升高了两种大鼠品系的LV一氧化氮和cGMP水平。这些结果表明，激肽释放酶-激肽通过抑制JNK、TGF-β 1和纤溶酶原激活物抑制剂-1经由一氧化氮-cGMP途径减轻SHR的心脏肥大和纤维化，并增强毛细血管生长。
Hypertension that results in left ventricular (LV) hypertrophy and/or fibrosis can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. To investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, an adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar-Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 wk, but had no effect from 3 to 5 wk. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV-to-heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes after kallikrein gene transfer were associated with decreases in JNK activation as well as transforming growth factor (TGF)-beta1 and plasminogen activator inhibitor-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-beta1, and plasminogen activator inhibitor-1 via the nitric oxide-cGMP pathway.