REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN CARDIAC MYOCYTES
REGULATION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR IN CARDIAC MYOCYTES
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DOI：
10.1161/01.res.76.5.758
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发表时间：
1995-05-01
影响因子：
20.1
通讯作者：
GOLDBERG, MA
中科院分区：
文献类型：
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作者：
LEVY, AP;LEVY, NS;GOLDBERG, MA
侧支血管补充正常的冠状动脉血流量和冠状动脉疾病损害的冠状动脉血流量，从而保护心肌免受缺血。侧支血管形成是血管生成的结果。血管内皮生长因子（VEGF），也称为血管通透性因子（VPF），是一种分泌的内皮细胞特异性有丝分裂原，是一种非常有效的血管生成因子。在本研究中，VPF/VEGF的mRNA和蛋白质被证明是显着刺激在原代大鼠心肌细胞在体外响应于氧张力降低到1%或抑制电子传递链。VPF/VEGF的四种亚型协同调节缺氧，包括一个新的亚型以前没有描述。佛波酯和去极化剂藜芦碱，蛋白激酶C和钙内流的刺激剂，分别被发现显着增加心肌细胞VPF/VEGF mRNA的表达。毛喉素，一个有效的刺激剂的腺苷酸环化酶，产生了一个小的，但显着增加VPF/VEGF mRNA的表达在心肌细胞。但只有蛋白激酶C抑制剂H7能抑制低氧诱导的VPF/VEGF mRNA表达，钙内流抑制剂、钙-钙调蛋白依赖性蛋白激酶II抑制剂和蛋白激酶A抑制剂不能阻断低氧诱导的VPF/VEGF mRNA表达。这表明，不止一个信号转导通路参与调节VPF/VEGF表达。调节低氧反应基因表达的传感器被认为是血红素蛋白。与此模型相一致，过渡金属启动了一个类似于缺氧的遗传程序。在本研究中，过渡金属钴和锰增加VPF/VEGF mRNA在心肌细胞在体外和心肌组织在体内，提供了证据，类似的传感器可以调节VPF/VEGF在心肌细胞。这些数据表明，VPF/VEGF诱导有助于缺血心肌侧支血管形成的一种新机制，并提出了增加体内VPF/VEGF产生的策略。
Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia. In the present study, the transition metals cobalt and manganese increased VPF/VEGF mRNA in cardiac myocytes in vitro and myocardial tissue in vivo, providing evidence that a similar sensor may regulate VPF/VEGF in the cardiac myocyte. These data suggest a novel mechanism by which VPF/VEGF induction contributes to collateral vessel formation in ischemic myocardium and also suggest strategies to increase VPF/VEGF production in vivo.