Cardioprotection mediated by rosiglitazone, a peroxisome proliferatoractivated receptor gamma ligand, in relation to nitric oxide
Cardioprotection mediated by rosiglitazone, a peroxisome proliferatoractivated receptor gamma ligand, in relation to nitric oxide
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DOI：
10.1007/s00395-006-0613-4
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发表时间：
2007-01-01
影响因子：
9.5
通讯作者：
Pernow, John
中科院分区：
文献类型：
--
作者：
Gonon, Adrian T.;Bulhak, Aliaksandr;Pernow, John
激活过氧化物酶体增殖物激活受体（PPAR）γ可保护心肌免受缺血/再灌注损伤。本研究的目的是研究PPARgamma的心脏保护作用是否与一氧化氮（NO）有关。方法野生型（WT）和内皮型一氧化氮合酶（eNOS）基因敲除（KO）小鼠分别给予3 mg/kg的PPAR γ激动剂罗格列酮或溶媒（每组6-9只）i. p.麻醉前45分钟。分离心脏，以Langendorff模式灌注，并进行全脑缺血和30 min再灌注。另外两组WT小鼠的心脏除了接受溶剂或罗格列酮预处理外，还接受NOS抑制剂L-NNA（100 μ mol/l）或溶剂。结果罗格列酮能促进WT心脏缺血后左室功能和冠脉流量的恢复，L-NNA本身对恢复无影响，但能显著减弱罗格列酮对左室功能恢复的促进作用。在KO组，罗格列酮抑制缺血后心肌功能的恢复。罗格列酮对WT心肌eNOS的表达无影响，但能显著增加eNOS磷酸化水平（P < 0.05）。结论PPARgamma激动剂罗格列酮的心肌保护作用可能是通过磷酸化eNOS介导的。
Activation of peroxisome proliferator-activated receptor (PPAR) gamma protects from myocardial ischemia/reperfusion injury. The aim of the study was to investigate whether the cardioprotective effect of PPARgamma is related to nitric oxide (NO). Methods Wild type (WT) and endothelial NO synthase (eNOS) knockout (KO) mice received 3 mg/kg of the PPARgamma agonist rosiglitazone or vehicle (n = 6-9 in each group) i. p. 45 min before anesthesia. The hearts were isolated, perfused in a Langendorff mode and subjected to global ischemia and 30 min reperfusion. The hearts of another two groups of WT mice received the NOS inhibitor L-NNA (100 mu mol/l) or vehicle in addition to pre-treatment with vehicle or rosiglitazone. Results In the WT heart, rosiglitazone increased the recovery of left ventricular function and coronary flow following ischemia in comparison with the vehicle group.L-NNA did not affect recovery per se but significantly blunted the improvement in the recovery of left ventricular function induced by rosiglitazone. In the KO group rosiglitazone suppressed the recovery of myocardial function following ischemia. Expression of eNOS was not affected, but phosphorylated eNOS was significantly increased by rosiglitazone in the WT hearts (P < 0.05). Conclusions These results suggest that the cardioprotective effect of the PPARgamma agonist rosiglitazone is mediated via NO by phosphorylation of eNOS.