Rocic Petra, Kolz Christopher, Reed Ryan, Potter Barry, Chilian William M
Department of Physiology, Louisiana State Univeristy Health Sciences Center, New Orleans, Louisiana, USA.
Am J Physiol Heart Circ Physiol. 2007 Jun;292(6):H2729-36. doi: 10.1152/ajpheart.01330.2006. Epub 2007 Feb 16.
Reactive oxygen species (ROS) are implicated in coronary collateral growth (CCG). We evaluated the requirement for ROS in human coronary artery endothelial cell (HCAEC) tube formation, CCG in vivo, and signaling (p38 MAP kinase) by which ROS may stimulate vascular growth. The flavin-containing oxidase inhibitor diphenyleneiodonium (DPI) or the superoxide dismutase inhibitor diethyldithiocarbamate (DETC) blocked vascular endothelial growth factor-induced HCAEC tube formation in Matrigel. We assessed the effect of DPI and DETC on CCG in a rat model of repetitive ischemia (RI) (40 s left anterior descending coronary artery occlusion every 20 min for 2 h 20 min, 3 times/day, 10 days). DPI or DETC was given intraperitoneally, or the NAD(P)H oxidase inhibitor apocynin was given in drinking water. Collateral-dependent flow (measured by using microspheres) was expressed as a ratio of normal and ischemic zone flows. In sham-operated rats, collateral flow in the ischemic zone was 18 +/- 6% of normal zone; in the RI group, collateral flow in the ischemic zone was 83 +/- 5% of normal zone. DPI prevented the increase in collateral flow after RI (25 +/- 4% of normal zone). Similar results were obtained with apocynin following RI (32 +/- 7% of that in the normal zone). DETC achieved similar results (collateral flow after RI was 21 +/- 2% of normal zone). DPI and DETC blocked RI-induced p38 MAP kinase activation in response to vascular endothelial growth factor and RI. These results demonstrate a requirement for optimal ROS concentration in HCAEC tube formation, CCG, and p38 MAP kinase activation. p38 MAP kinase inhibition prevented HCAEC tube formation and partially blocked RI-induced CCG (42 +/- 7% of normal zone flow), indicating that p38 MAP kinase is a critical signaling mediator of CCG.
活性氧（ROS）与冠状动脉侧支循环生长（CCG）有关。我们评估了在人冠状动脉内皮细胞（HCAEC）形成管腔、体内CCG以及ROS可能刺激血管生长的信号传导（p38丝裂原活化蛋白激酶）过程中对ROS的需求。含黄素氧化酶抑制剂二苯碘鎓（DPI）或超氧化物歧化酶抑制剂二乙基二硫代氨基甲酸盐（DETC）可阻断血管内皮生长因子诱导的HCAEC在基质胶中形成管腔。我们评估了DPI和DETC对重复缺血（RI）大鼠模型（每20分钟左冠状动脉前降支闭塞40秒，共2小时20分钟，每天3次，持续10天）中CCG的影响。DPI或DETC通过腹腔注射给药，或者NAD（P）H氧化酶抑制剂夹竹桃麻素通过饮用水给药。侧支循环依赖性血流（通过微球测量）表示为正常区域血流与缺血区域血流的比值。在假手术大鼠中，缺血区域的侧支循环血流为正常区域的18±6%；在RI组中，缺血区域的侧支循环血流为正常区域的83±5%。DPI阻止了RI后侧支循环血流的增加（为正常区域的25±4%）。RI后给予夹竹桃麻素也得到了类似结果（为正常区域的32±7%）。DETC也得到了类似结果（RI后侧支循环血流为正常区域的21±2%）。DPI和DETC阻断了RI诱导的p38丝裂原活化蛋白激酶对血管内皮生长因子和RI的激活。这些结果表明，在HCAEC形成管腔、CCG以及p38丝裂原活化蛋白激酶激活过程中需要最佳的ROS浓度。抑制p38丝裂原活化蛋白激酶可阻止HCAEC形成管腔，并部分阻断RI诱导的CCG（为正常区域血流的42±7%），这表明p38丝裂原活化蛋白激酶是CCG的关键信号传导介质。
