Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A12-26
Reperfusion-induced myocardial dysfunction is prevented by endogenous annexin-A1 and its N-terminal-derived peptide Ac-ANX-A12-26
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DOI：
10.1111/j.1476-5381.2012.02176.x
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发表时间：
2013-01-01
影响因子：
7.3
通讯作者：
Ritchie, Rebecca H.
中科院分区：
文献类型：
--
作者：
Qin, Chengxue;Buxton, Keith D.;Ritchie, Rebecca H.
背景与目的膜联蛋白-A1（Annexin-A1，ANX-A1）是一种内源性糖皮质激素调节的抗炎蛋白。N-末端衍生肽Ac-ANX-A1226保留心肌细胞活力，但ANX-A1-肽对心肌收缩力的影响尚不清楚。我们现在检验ANX-A1保留左心室（LV）功能缺血后恢复的假设。实验方法在再灌注时，将Ac-ANX-A1226给予成年大鼠心肌细胞以及从大鼠、野生型小鼠和内源性ANX-A1缺陷小鼠（ANX-A1/）分离的心脏。测定心肌存活率和左室功能恢复情况。缺血再灌注显著损害心肌细胞活力和左室功能恢复60%。在再灌注开始时用外源性Ac-ANX-A1226治疗防止了心肌细胞损伤，并显著改善了完整大鼠和野生型小鼠心脏的LV功能恢复。Ac-ANX-A1226的心脏保护作用被甲酰肽受体（FPR）非选择性或FPR 1选择性拮抗剂Boc 2和环孢菌素H消除，但对FPR 2选择性拮抗剂QuinC 7相对不敏感。ANX-A1诱导的心脏保护作用与细胞存活激酶Akt的磷酸化增加有关。除了选择性LV FPR 1下调外，ANX-A1-/-加重了缺血后LV功能恢复的损害。这些数据代表了ANX-A1影响心肌功能的第一个证据。我们的研究结果表明ANX-A1是缺血后LV功能恢复的内源性调节因子。此外，ANX-A1衍生肽Ac-ANX-A1226在再灌注时可能通过激活FPR 1挽救LV功能。因此，基于ANX-A1的治疗可能代表了预防和治疗心肌再灌注损伤的新临床方法。
BACKGROUND AND PURPOSE Annexin-A1 (ANX-A1) is an endogenous, glucocorticoid-regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A1226 preserves cardiomyocyte viability, but the impact of ANX-A1-peptides on cardiac contractility is unknown. We now test the hypothesis that ANX-A1 preserves post-ischaemic recovery of left ventricular (LV) function. EXPERIMENTAL APPROACH Ac-ANX-A1226 was administered on reperfusion, to adult rat cardiomyocytes as well as hearts isolated from rats, wild-type mice and mice deficient in endogenous ANX-A1 (ANX-A1/). Myocardial viability and recovery of LV function were determined. KEY RESULTS Ischaemiareperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A1226 at the onset of reperfusion prevented cardiomyocyte injury and significantly improved recovery of LV function, in both intact rat and wild-type mouse hearts. Ac-ANX-A1226 cardioprotection was abolished by either formyl peptide receptor (FPR)-nonselective or FPR1-selective antagonists, Boc2 and cyclosporin H, but was relatively insensitive to the FPR2-selective antagonist QuinC7. ANX-A1-induced cardioprotection was associated with increased phosphorylation of the cell survival kinase Akt. ANX-A1-/- exaggerated impairment of post-ischaemic recovery of LV function, in addition to selective LV FPR1 down-regulation. CONCLUSIONS AND IMPLICATIONS These data represent the first evidence that ANX-A1 affects myocardial function. Our findings suggest ANX-A1 is an endogenous regulator of post-ischaemic recovery of LV function. Furthermore, the ANX-A1-derived peptide Ac-ANX-A1226 on reperfusion rescues LV function, probably via activation of FPR1. ANX-A1-based therapies may thus represent a novel clinical approach for the prevention and treatment of myocardial reperfusion injury.