Baker IDI Heart & Diabetes Institute, Melbourne, Australia.
Br J Pharmacol. 2013 Jan;168(1):238-52. doi: 10.1111/j.1476-5381.2012.02176.x.
Annexin-A1 (ANX-A1) is an endogenous, glucocorticoid-regulated anti-inflammatory protein. The N-terminal-derived peptide Ac-ANX-A1(2-26) 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.
Ac-ANX-A1(2-26) 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.
Ischaemia-reperfusion markedly impaired both cardiomyocyte viability and recovery of LV function by 60%. Treatment with exogenous Ac-ANX-A1(2-26) 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-A1(2-26) 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.
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-A1(2-26) 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.
膜联蛋白 A1（ANX-A1）是一种内源性、糖皮质激素调节的抗炎蛋白。其 N 端衍生肽 Ac-ANX-A1（2-26）可维持心肌细胞活力，但 ANX-A1 肽对心肌收缩力的影响尚不清楚。我们现通过实验验证假设，即 ANX-A1 可维持左心室（LV）功能在缺血后的恢复。
将 Ac-ANX-A1（2-26）在再灌注时给予成年大鼠心肌细胞以及来自大鼠、野生型小鼠和内源性 ANX-A1 缺乏（ANX-A1（-/-））小鼠的心脏。测定心肌活力和 LV 功能的恢复情况。
缺血再灌注明显损害了心肌细胞活力和 LV 功能的恢复，分别达到 60%。再灌注起始时给予外源性 Ac-ANX-A1（2-26）可预防心肌损伤，并显著改善完整大鼠和野生型小鼠心脏的 LV 功能恢复。Boc2 和环孢菌素 H（FPR1 选择性拮抗剂）以及 QuinC7（FPR2 选择性拮抗剂）可完全阻断 Ac-ANX-A1（2-26）的心脏保护作用，但对 FPR2 选择性拮抗剂相对不敏感。ANX-A1 诱导的心脏保护与细胞存活激酶 Akt 的磷酸化增加有关。除了选择性 LV FPR1 下调外，ANX-A1（-/-）还加重了缺血后 LV 功能恢复的损害。
这些数据代表了 ANX-A1 影响心肌功能的首个证据。我们的研究结果表明，ANX-A1 是调节缺血后 LV 功能恢复的内源性调节剂。此外，再灌注时给予 ANX-A1 衍生肽 Ac-ANX-A1（2-26）可挽救 LV 功能，可能是通过激活 FPR1。因此，基于 ANX-A1 的治疗方法可能为预防和治疗心肌再灌注损伤提供一种新的临床方法。
