Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2
Lead-induced downregulation of soluble guanylate cyclase in isolated rat aortic segments mediated by reactive oxygen species and cyclooxygenase-2
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DOI：
10.1097/01.asn.0000064947.14997.69
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发表时间：
2003-06-01
影响因子：
13.6
通讯作者：
López-Farré, A
中科院分区：
文献类型：
--
作者：
Courtois, E;Marques, M;López-Farré, A
铅暴露是高血压的一个已知原因。虽然大多数研究都集中在铅诱导的内皮功能障碍和活性氧（ROS）的参与，它最近已被证明，铅暴露大鼠的血管壁既改变了内皮非依赖性舒张反应和可溶性鸟苷酸环化酶（sGC）的表达减少。本研究的目的是确定在体外培养的大鼠离体主动脉节段，如果铅下调sGC的表达，分析参与的ROS和环氧合酶-2（考克斯-2）。实验在离体Wistar大鼠主动脉节段中进行，所述离体主动脉节段与铅孵育24小时。铅以浓度依赖性方式显著降低sGC-β（1）亚基表达。1 ppm铅可使sGC-β（1）亚基表达最大程度降低。维生素C（30 μ mol/L）部分恢复铅（1 ppm）暴露的主动脉节段中sGC-β 1亚基的表达。蛋白激酶A抑制剂H89（1 μ mol/L）和考克斯-2活性抑制剂罗非昔布（1 μ mol/L）对sGC-β（1）亚基表达的保护作用相似。此外，铅暴露增加动脉壁中的考克斯-2表达。虽然维生素C降低了与铅暴露相关的考克斯-2表达和超氧阴离子的产生，但罗非昔布未能改变铅孵育主动脉节段中超氧阴离子的产生。上述结果提示，ROS和考克斯-2参与了铅诱导的大鼠血管壁sGC-β 1亚基表达的下调。
Lead exposure is a known cause of hypertension. Although most studies have focused on lead-induced endothelial dysfunction and on the involvement of reactive oxygen species (ROS), it has been recently demonstrated that the vascular wall of lead-exposed rats has both an altered the endothelium-independent relaxing response and a reduced expression of soluble guanylate cyclase (sGC). The aim of the present study was to determine in in vitro incubated rat isolated aortic segments if lead downregulates sGC expression, analyzing the involvement of ROS and cyclooxygenase-2 (COX-2). The experiments were performed in isolated aortic segments from Wistar rats that were incubated with lead for 24 h. Lead significantly reduced sGC-beta(1) subunit expression in a concentration-dependent manner. The maximal reduction in sGC-beta(1) subunit expression was achieved with 1 ppm lead. Vitamin C (30 mumol/L) partially restored sGC-beta1 subunit expression in lead (1 ppm)-exposed aortic segments. A similar protection of sGC-beta(1) subunit expression was obtained with both a protein kinase A inhibitor, H89 (1 mumol/L) and with rofecoxib (1 mumol/L), an inhibitor of COX-2 activity. Moreover, lead exposure increased COX-2 expression in the arterial wall. While vitamin C reduced both COX-2 expression and superoxide anion production related to lead exposure, rofecoxib failed to modify superoxide anion generation in lead-incubated aortic segments. In conclusion, the present results suggest the involvement of ROS and COX-2 in the downexpression of sGC-beta(1) subunit induced by lead in the rat vascular wall.