Parstatin: a cryptic peptide involved in cardioprotection after ischaemia and reperfusion injury.
Parstatin: a cryptic peptide involved in cardioprotection after ischaemia and reperfusion injury.
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帕他汀：一种神秘的肽，参与缺血和再灌注损伤后的心脏保护。
DOI：
10.1093/cvr/cvp122
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发表时间：
2009
影响因子：
10.8
通讯作者：
Baker,JohnE
中科院分区：
文献类型：
--
作者：
Strande,JenniferL;Widlansky,MichaelE;Tsopanoglou,NikosE;Su,Jidong;Wang,JingLi;Hsu,Anna;Routhu,KasiV;Baker,JohnE
目的凝血酶通过N末端的蛋白水解性裂解激活蛋白酶激活的受体1。虽然许多研究都集中在激活的受体上，但对41个氨基酸的N端肽(Parstatin)却知之甚少。我们假设parstatin对心肌缺血再灌注损伤有保护作用。方法和结果我们在活体和体外心肌缺血再灌注损伤模型中评价了parstatin的保护作用。在缺血-再灌注损伤的活体模型中，缺血前、缺血中和缺血后的Parstatin治疗分别使梗塞面积减少了26%、23%和18%。在Anin体外模型中，缺血前立即给予Parstatin治疗可使梗塞面积减少65%，并使心功能恢复增加23%。然后，我们评估了parstatin是否通过激活依赖于Gi蛋白的途径来诱导心脏保护。百日咳毒素灭活胃肠道蛋白可完全消除其心脏保护作用。体外抑制一氧化氮合酶(NOS)、细胞外信号调节激酶1/2(ERK1/2)、p38丝裂原活化蛋白激酶(P38 MAPK)和KATP通道也可取消其心肌保护作用。此外，parstatin增加了冠脉流量，降低了离体心的灌流压。结论在大鼠冠状动脉缺血前单独应用parstatin可通过重新启动包括p38MAPK、ERK1/2、NOS和KATP通道在内的GI蛋白激活通路，提供即刻的心脏保护作用。Parstatin对心肌细胞和冠脉循环都有作用，从而诱导心脏保护。这提示Parstatin在治疗心肌缺血和再灌注损伤中具有潜在的治疗作用。
AimsThrombin activates protease-activated receptor 1 by proteolytic cleavage of the N-terminus. Although much research has focused on the activated receptor, little is known about the 41-amino acid N-terminal peptide (parstatin). We hypothesized that parstatin would protect the heart against ischaemia–reperfusion injury.Methods and resultsWe assessed the protective role of parstatin in anin vivoandin vitrorat model of myocardial ischaemia–reperfusion injury. Parstatin treatment before, during, and after ischaemia decreased infarct size by 26%, 23%, and 18%, respectively, in anin vivomodel of ischaemia–reperfusion injury. Parstatin treatment immediately before ischaemia decreased infarct size by 65% and increased recovery in ventricular function by 23% in anin vitromodel. We then assessed whether parstatin induced cardioprotection by activation of a Gi-protein-dependent pathway. Gi-protein inactivation by pertussis toxin completely abolished the cardioprotective effects. The cardioprotective effects were also abolished by inhibition of nitric oxide synthase (NOS), extracellular signal-regulated kinases 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), and KATPchannelsin vitro. Furthermore, parstatin increased coronary flow and decreased perfusion pressure in the isolated heart. The vasodilatory properties of parstatin were confirmed in rat coronary arterioles.ConclusionA single treatment of parstatin administered prior to ischaemia confers immediate cardioprotection by recruiting the Gi-protein activation pathway including p38 MAPK, ERK1/2, NOS, and KATPchannels. Parstatin exerts effects on both the cardiomyocytes and the coronary circulation to induce cardioprotection. This suggests a potential therapeutic role of parstatin in the treatment of cardiac injury resulting from ischaemia and reperfusion.