Malhotra Sunil P, Reddy V Mohan, Thelitz Stephan, He You-Ping, McMullan D Michael, Hanley Frank L, Riemer R Kirk
Division of Cardiothoracic Surgery, University of California, San Francisco, Calif. 94305-5407, USA.
J Thorac Cardiovasc Surg. 2002 Sep;124(3):479-85. doi: 10.1067/mtc.2002.120346.
Cavopulmonary anastomosis is used for palliation of cyanotic heart disease. Clinically significant pulmonary arteriovenous malformations occur in up to 25% of patients after surgical intervention. Cavopulmonary anastomosis creates several modifications to pulmonary physiology that may contribute to the development of pulmonary arteriovenous malformations, including reduced pulmonary blood flow and the exclusion of inferior vena caval effluent.
By comparing the expression of angiogenic and stress-related proteins after cavopulmonary anastomosis and pulmonary artery banding, we sought to determine which genes were upregulated independent of reduced pulmonary blood flow.
Lambs aged 35 to 45 days were placed into 1 of 3 groups: cavopulmonary anastomosis (n = 6), pulmonary artery banding (n = 6), and sham control (n = 6) animals. In our model pulmonary arteriovenous malformations are detectable by means of bubble-contrast echocardiography 8 weeks after cavopulmonary anastomosis. Lung tissue was harvested for Western blotting at 2 and 5 weeks after surgery.
Cavopulmonary anastomosis and pulmonary artery banding both increased angiogenic gene expression, but only cavopulmonary anastomosis induced the expression of endothelial stress-related genes. Vascular endothelial growth factor was upregulated 2.5-fold after both cavopulmonary anastomosis (P =.002) and pulmonary artery banding (P =.007). Only cavopulmonary anastomosis upregulated 2 stress-related genes, HO1 and GLUT1, 2.7-fold (P =.002) and 3.8-fold (P =.03), respectively. Hypoxia-inducible factor was upregulated 4-fold (P =.003) after cavopulmonary anastomosis. Pulmonary artery banding failed to induce the increased expression of any of these proteins.
Reduced pulmonary blood flow induces a pulmonary angiogenic response but not an endothelial stress response. These results suggest that oxidative stress is more relevant to the formation of pulmonary arteriovenous malformations than angiogenic signaling alone because pulmonary artery banding does not result in pulmonary arteriovenous malformations. Oxidative stress of the pulmonary endothelium resulting from cavopulmonary anastomosis may predispose the affected vasculature to arteriovenous shunting.
腔肺吻合术用于治疗青紫型心脏病。在手术干预后，高达25%的患者会出现具有临床意义的肺动静脉畸形。腔肺吻合术对肺生理功能产生了多种改变，这可能有助于肺动静脉畸形的发展，包括肺血流量减少和下腔静脉血流排除。
通过比较腔肺吻合术和肺动脉环扎术后血管生成相关蛋白和应激相关蛋白的表达，我们试图确定哪些基因在肺血流量减少的情况下仍上调。
将35至45日龄的羔羊分为3组：腔肺吻合术组（n = 6）、肺动脉环扎术组（n = 6）和假手术对照组（n = 6）。在我们的模型中，腔肺吻合术后8周可通过气泡对比超声心动图检测到肺动静脉畸形。术后2周和5周采集肺组织进行蛋白质印迹分析。
腔肺吻合术和肺动脉环扎术均增加了血管生成基因的表达，但只有腔肺吻合术诱导了内皮应激相关基因的表达。腔肺吻合术（P =.002）和肺动脉环扎术（P =.007）后血管内皮生长因子均上调2.5倍。只有腔肺吻合术上调了2个应激相关基因，即HO1和GLUT1，分别上调2.7倍（P =.002）和3.8倍（P =.03）。腔肺吻合术后缺氧诱导因子上调4倍（P =.003）。肺动脉环扎术未能诱导这些蛋白中任何一种的表达增加。
肺血流量减少会诱导肺血管生成反应，但不会诱导内皮应激反应。这些结果表明，氧化应激比单独的血管生成信号传导与肺动静脉畸形的形成更相关，因为肺动脉环扎术不会导致肺动静脉畸形。腔肺吻合术导致的肺内皮氧化应激可能使受影响的血管系统易发生动静脉分流。
