Infanger Manfred, Faramarzi Shideh, Grosse Jirka, Kurth Ekkehard, Ulbrich Claudia, Bauer Johann, Wehland Markus, Kreutz Reinhold, Kossmehl Peter, Paul Martin, Grimm Daniela
Department of Trauma and Reconstructive Surgery, Charité-Universitätsmedizin Berlin, Benjamin Franklin Campus, 12203, Berlin, Germany.
Cardiovasc Pathol. 2007 Sep-Oct;16(5):291-9. doi: 10.1016/j.carpath.2007.04.001. Epub 2007 Jun 20.
Vascular endothelial growth factor (VEGF) expression is regulated by hypoxia and cytokines, including insulin-like growth factor (IGF)-1. We examined the influence of ischemia/reperfusion (I/R) on IGF-1, VEGF, fetal liver kinase (flk-1), fms-like tyrosine kinase-1 (flt-1), and laminin using an isolated hemoperfused working porcine heart model of acute ischemia (2 h) and reperfusion (4 h).
Twenty-three porcine hearts were randomized into the following groups: five nonischemic control hearts (Group C), five I/R hearts with occlusion of the ramus circumflexus; three I/R hearts treated with quinaprilat, a potent angiotensin-converting enzyme (ACE) inhibitor (Group Q); five I/R hearts treated with angiotensin I (Group Ang I), and 5 I/R hearts treated with Ang I and quinaprilat (Group QA).
Compared to C, VEGF mRNA and protein contents were significantly increased in I/R and Ang I hearts. flk-1 and flt-1 were increased in I/R (2.2-/1.95-fold) and further elevated by Ang I (3.2-/3.4-fold) compared with C. Quinaprilat application attenuated the amount of VEGF significantly and of flk-1 slightly but not that of flt-1. In contrast, IGF-1 and IGF-1 receptor (IGF-1R) proteins were elevated in I/R hearts (3-/1.4-fold vs. C) and further increased in the presence of Q. These findings were accompanied by an elevation of laminin mRNA and protein levels. Moreover, we observed an increase in collagen Type IV and chondroitin sulfate content in I/R (2.9-/1.4-fold) and Ang I (3.5-/1.5-fold) hearts. Quinaprilat significantly reduced laminin and chondroitin sulfate proteins.
These data suggest that the VEGF/VEGF receptor and IGF-1-IGF-1R systems are activated by I/R. The benefits of ACE inhibition in attenuation of cardiac remodeling may be mediated by IGF-1.
血管内皮生长因子（VEGF）的表达受缺氧和细胞因子调节，包括胰岛素样生长因子（IGF）-1。我们使用急性缺血（2小时）和再灌注（4小时）的离体血液灌注工作猪心脏模型，研究了缺血/再灌注（I/R）对IGF-1、VEGF、胎儿肝激酶（flk-1）、fms样酪氨酸激酶-1（flt-1）和层粘连蛋白的影响。
将23个猪心脏随机分为以下几组：5个非缺血对照心脏（C组），5个左旋支闭塞的I/R心脏；3个用强效血管紧张素转换酶（ACE）抑制剂喹那普利拉治疗的I/R心脏（Q组）；5个用血管紧张素I治疗的I/R心脏（Ang I组），以及5个用血管紧张素I和喹那普利拉治疗的I/R心脏（QA组）。
与C组相比，I/R组和Ang I组心脏中VEGF mRNA和蛋白含量显著增加。与C组相比，I/R组中flk-1和flt-1增加（2.2倍/1.95倍），Ang I组进一步升高（3.2倍/3.4倍）。应用喹那普利拉可显著降低VEGF含量，轻微降低flk-1含量，但对flt-1含量无影响。相反，I/R组心脏中IGF-1和IGF-1受体（IGF-1R）蛋白升高（与C组相比为3倍/1.4倍），在有喹那普利拉的情况下进一步增加。这些发现伴随着层粘连蛋白mRNA和蛋白水平的升高。此外，我们观察到I/R组（2.9倍/1.4倍）和Ang I组（3.5倍/1.5倍）心脏中IV型胶原和硫酸软骨素含量增加。喹那普利拉显著降低层粘连蛋白和硫酸软骨素蛋白含量。
这些数据表明，VEGF/VEGF受体和IGF-1-IGF-1R系统被I/R激活。ACE抑制在减轻心脏重塑方面的益处可能由IGF-1介导。
