A novel strategy for myocardial protection by combined antibody therapy inhibiting both P-selectin and intercellular adhesion molecule-1 via retrograde intracoronary route
A novel strategy for myocardial protection by combined antibody therapy inhibiting both P-selectin and intercellular adhesion molecule-1 via retrograde intracoronary route
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DOI：
10.1161/circulationaha.105.000794
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发表时间：
2006-07-04
期刊：
影响因子：
37.8
通讯作者：
Suzuki, Ken
中科院分区：
文献类型：
--
作者：
Fukushima, Satsuki;Coppen, Steven R.;Suzuki, Ken
背景：据报道，抑制p -选择素或细胞间粘附分子-1 （ICAM-1）的抗体治疗可保护心肌免受白细胞介导的再灌注损伤。由于这些分子在白细胞-内皮相互作用中发挥着不同的作用，因此共同抑制两者可能进一步增强心脏保护作用。此外，这种抗体疗法的治疗效果可能受到所使用的递送途径的影响。逆行冠状动脉内输注将提供一个有效的，直接进入毛细血管后小静脉的途径，在那里目标事件（白细胞内皮相互作用）发生。我们研究了经逆行冠状动脉内途径同时靶向p -选择和ICAM-1的联合抗体治疗减轻心肌缺血再灌注损伤的可行性和有效性。方法与结果：lewis大鼠左冠状动脉闭塞30分钟。再灌注前将抗p -选择素单克隆抗体（150 μ g/kg）、抗icam -1单克隆抗体（200 μ g/kg）、两种抗体联合或对照抗体逆行输注左心静脉。再灌注后24小时，与对照组（56.8 +/- 3.4%）相比，抗P-选择素或抗icam -1抗体均显著（P < 0.05）改善左室射血分数（40.6 +/- 3.2%）和缩小梗死面积（34.8 +/- 3.5%）。这与减少白细胞积累和改善局部缺血区域血流有关。值得注意的是，与单独使用任一抗体相比，两种抗体联合使用可显著降低梗死面积（19.1 +/- 3.6%），并伴有白细胞浸润的更大衰减。结论经逆行冠状动脉内途径抑制p -选择素和ICAM-1的联合抗体治疗可能是一种有希望的心肌缺血再灌注保护新策略。
Background-Antibody therapy to inhibit either P-selectin or intercellular adhesion molecule-1 (ICAM-1) has been reported to provide myocardial protection against leukocyte-mediated reperfusion injury. Because these molecules play different roles in the leukocyte-endothelial interaction, co-inhibition of both may achieve further enhanced cardioprotection. In addition, the therapeutic efficacy of such antibody therapy may be affected by the delivery route used. Retrograde intracoronary infusion will offer an effective, direct access to the postcapillary venules, where the target event (leukocyte-endothelial interaction) takes place. We investigated the feasibility and efficiency of the combined antibody therapy targeting both P-selection and ICAM-1 via the retrograde intracoronary route to attenuate myocardial ischemia-reperfusion injury.Methods and Results-Lewis rats underwent 30-minute left coronary artery occlusion. Just before reperfusion, anti-P-selectin monoclonal antibody (150 mu g/kg), anti-ICAM-1 monoclonal antibody (200 mu g/kg), both antibodies together, or control antibody were retrogradely infused into the left cardiac vein. At 24 hours after reperfusion, administration of either anti-P-selectin or anti-ICAM-1 antibody significantly (P < 0.05) improved left ventricular ejection fraction and attenuated infarct size (40.6 +/- 3.2% and 34.8 +/- 3.5%, respectively) compared with the control (56.8 +/- 3.4%). This was associated with reduced leukocyte accumulation and improved regional blood flow in the ischemic area. Noticeably, co-administration of both antibodies achieved a much greater reduction in infarct size (19.1 +/- 3.6%), associated with greater attenuation in leukocyte infiltration, compared with administration of either single antibody.Conclusions-Combined antibody therapy inhibiting both P-selectin and ICAM-1 via the retrograde intracoronary route could be a promising new strategy for myocardial protection against ischemia-reperfusion injury.