Oral Administration of Geranylgeranylacetone Blunts the Endothelial Dysfunction Induced by Ischemia and Reperfusion in the Rat Heart
Oral Administration of Geranylgeranylacetone Blunts the Endothelial Dysfunction Induced by Ischemia and Reperfusion in the Rat Heart
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DOI：
10.1097/01.fjc.0000159879.04444.22
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发表时间：
2005-06
影响因子：
3
通讯作者：
Zhen-long Zhu;N. Takahashi;T. Ooie;T. Shinohara;Kunitoshi Yamanaka;T. Saikawa
中科院分区：
文献类型：
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作者：
Zhen-long Zhu;N. Takahashi;T. Ooie;T. Shinohara;Kunitoshi Yamanaka;T. Saikawa
研究表明，香叶基香叶基丙酮 (GGA) 通过增强大鼠热休克蛋白 72 (HSP72) 的表达来保护心脏免受缺血/再灌注损伤。在本研究中，我们研究了 GGA 对缺血/再灌注引起的内皮功能障碍的保护作用。给大鼠口服GGA（GGA组）或载体（CON组），24小时后取出心脏并放入Langendorff装置中进行30分钟低流量缺血，然后再灌注30分钟。 GGA 改善了缺血后功能恢复（P < 0.01），而 NG-硝基-L-精氨酸甲酯（L-NAME，NO 合酶抑制剂）可消除这种功能恢复。 GGA 组在缺血和再灌注期间 NO 产生均增加，并且与 CON 组 (7.9 ± 1.4%) 相比，乙酰胆碱 (ACh) 诱导的（内皮依赖性）血管舒张（以缺血/再灌注后冠状动脉灌注压下降的百分比衡量）得以保留 (14.9 ± 1.3%)。 LY294002（一种磷脂酰肌醇3（PI3）激酶抑制剂）消除了GGA对内皮依赖性冠状动脉舒张和NO产生的保护作用，而Y27632（Rho激酶抑制剂）使CON组内皮依赖性冠状血管舒张和NO产生增加至GGA组的水平。基础条件下GGA组冠状动脉流出液中肾上腺髓质素含量低于CON组（P < 0.05），并且在缺血和再灌注期间GGA和CON组之间肾上腺髓质素含量没有差异。此外，GGA 组和 CON 组之间的内皮素-1 量没有观察到差异。这些结果表明，GGA 可以减轻缺血/再灌注引起的冠状动脉内皮功能障碍，这可能有助于其心脏保护作用。 PI3 激酶和/或 Rho 激酶途径似乎参与了这一过程，而肾上腺髓质素和内皮素-1 对于 GGA 诱导的心脏保护作用不是必需的。
It has been shown that geranylgeranylacetone (GGA) protects heart against ischemia/reperfusion injury via enhanced heat shock protein 72 (HSP72) expression in rats. In the present study, we investigated the protective effect of GGA on ischemia/reperfusion-induced endothelial dysfunction. Rats were given oral GGA (GGA group) or vehicle (CON group), and 24 hours later their hearts were removed and placed in the Langendorff apparatus for 30-minute low-flow ischemia followed by 30-minute reperfusion. GGA improved the postischemic functional recovery (P < 0.01), which was abolished by NG-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor). NO production during both ischemia and reperfusion were increased in the GGA group, and the acetylcholine (ACh)-induced (endothelium-dependent) vasodilation, measured as the percentage decrease in coronary perfusion pressure after ischemia/reperfusion (14.9 ± 1.3%), was preserved as compared with that in the CON group (7.9 ± 1.4%). LY294002, a phosphatidylinositol 3 (PI3) kinase inhibitor, abolished the protective effects of GGA on endothelial-dependent coronary vasodilation and NO production, whereas Y27632 (Rho kinase inhibitor) increased endothelium-dependent coronary vasodilation and NO production in CON group toward the level seen in GGA group. The amount of adrenomedullin in the coronary effluent at basal condition was lower in the GGA group than in the CON group (P < 0.05), and during both ischemia and reperfusion there was no difference in the amount of adrenomedullin between the GGA and CON groups. In addition, no difference was observed in the amount of endothelin-1 between the GGA and CON groups. These results indicate that GGA attenuates the ischemia/reperfusion-induced coronary endothelial dysfunction, which may contribute to its cardioprotective effect. The PI3 kinase and/or Rho kinase pathways appear to be involved in this process, whereas adrenomedullin and endothelin-1 are not necessary for the GGA-induced cardioprotection.