Adeno-associated virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs
Adeno-associated virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs
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DOI：
10.1161/01.res.0000217342.83731.89
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发表时间：
2006-04-14
影响因子：
20.1
通讯作者：
Hintze, TH
中科院分区：
文献类型：
--
作者：
Ferrarini, M;Arsic, N;Hintze, TH
我们以前已经表明，VEGF 165基因传递到缺血骨骼肌发挥不仅促血管生成，但也显着的抗凋亡和proregenerative活性。本研究的目的是确定重组腺相关病毒（rAAV）介导的VEGF 165基因进入心肌，在急性心肌梗死，发挥保护作用，促进长期功能恢复。在12只慢性内固定犬中，通过永久性闭塞LAD冠状动脉诱导左室前壁急性梗死。闭塞后4小时，用超声引导针将rAAV-VEGF 165或rAAV-LacZ（每种n = 6;每只动物5 × 10（12）个病毒颗粒）直接注射到功能障碍的心脏壁中。随着时间的推移，两组之间的LV和动脉压、dP/dt（max）和射血分数无显著差异。相比之下，在梗死区域，梗死后4周，VEGF 165与LacZ的缩短分数分别为基线的75 +/- 18%和- 3 +/- 15%，长度-压力面积分别为基线的54 +/- 15%和0.8 +/- 15%（P < 0.05）。边缘区域的组织学分析显示，α-SMA阳性小动脉数量显著增加（LacZ和VEGF 165组中每个显微镜视野分别为68 +/- 2.8和100 +/- 3.8条血管; P < 0.05）。在两组中，受体VEGFR-2在存活的心肌细胞上弥散表达，并且在VEGF 165处理组中，心肌存活率始终显著改善，其中几个肌钙蛋白T表达心肌细胞显示增殖标记物PCNA的核阳性。总之，我们的研究结果表明，VEGF 165基因传递发挥了显着的有益作用，通过增强动脉生成和心肌细胞的活力在梗死心肌。
We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic, but also remarkable antiapoptotic and proregenerative activity. The aim of this study was to determine whether recombinant adeno-associated virus (rAAV)-mediated gene delivery of VEGF165 into cardiac muscle, during acute myocardial infarction, exerts a protective effect to promote long-term functional recovery. Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery. Four hours after occlusion, rAAV-VEGF165 or rAAV-LacZ ( n = 6 each; 5 x 10(12) viral particles per animal) was directly injected with an echo-guided needle into the dysfunctional cardiac wall. LV and arterial pressure, dP/dt(max), and ejection fraction were not significantly different between the two groups over time. In contrast, in the infarcted region, at four weeks after infarction, fractional shortening was 75 +/- 18% and - 3 +/- 15% of baseline and length- pressure area was 54 +/- 15% and 0.8 +/- 15% of baseline in VEGF165 versus LacZ, respectively ( P < 0.05). Histological analysis of the border regions showed a marked increase in the number of alpha-SMA-positive arterioles ( 68 +/- 2.8 versus 100 +/- 3.8 vessels per microscopic field in LacZ and VEGF165 group, respectively; P < 0.05). In both groups, the receptor VEGFR-2 was diffusely expressed on the surviving cardiomyocytes and, consistently, myocardial viability was significantly improved in the VEGF165-treated group, with several troponin T - expressing cardiomyocytes displaying nuclear positivity for the proliferation marker PCNA. Altogether, our results indicate that VEGF165 gene delivery exerts a marked beneficial action by enhancing both arteriologenesis and cardiomyocyte viability in infarcted myocardium.