Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart
Cardioprotective effects of a novel proteasome inhibitor following ischemia and reperfusion in the isolated perfused rat heart
复制标题
DOI：
10.1006/jmcc.1998.0880
复制
发表时间：
1999-02-01
影响因子：
5
通讯作者：
Lefer, AM
中科院分区：
文献类型：
--
作者：
Campbell, B;Adams, J;Lefer, AM
在多形核白细胞（PMN）存在的情况下缺血再灌注会导致心脏收缩功能障碍以及心肌损伤。这些影响在很大程度上是由于内皮功能障碍导致细胞粘附分子上调以及随后的中性粒细胞诱导的心脏损伤。蛋白酶体抑制剂 PS-519 已被证明可以减弱白细胞与内皮细胞的相互作用。我们测试了 PS-519 对缺血/再灌注中中性粒细胞介导的心脏功能障碍的影响。本研究探讨了 PS-519 在中性粒细胞依赖性离体灌注大鼠缺血 (I)（20 分钟）和再灌注 (R)（45 分钟）模型中的作用。将 PS-519（0.01、0.1、0.3、1.0 mg/kg）注射到灌注有 PMN 的 I/R 心脏中可改善冠脉流量，并保留左心室发展压 (LVDP) 和 +dP/dt max 作为心脏收缩功能的指标。在 1.0 mg/kg 剂量下，PS-519 处理的心脏的最终 LVDP 为初始值的 98 +/- 3%，而仅接受载体的 I/R 心脏的最终 LVDP 为 52 +/- 8%（P < 0.001）。此外，PS-519 显着降低了缺血心肌中 PMN 的积累，从未治疗心脏的 25.1 +/- 2.1 PMNs/mm(2) 降至 7.3 PMNs/mm(2)，并将冠状血管内皮上的 P-选择素表面表达从 7.lt0.30/u 减弱至 1.4 +/- 0.2% (P < 0.01)。这些结果证明 PS-519 是一种强效且有效的心脏保护剂，可抑制 P-选择素白细胞与内皮细胞的相互作用，并在心肌缺血和再灌注后保留心脏收缩功能和冠状动脉灌注。 (C) 1999 年学术出版社。
Ischemia followed by reperfusion in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction as well as myocardial injury. These effects are due in large part to endothelial dysfunction leading to an upregulation of cell adhesion molecules and subsequent neutrophil induced cardiac injury. The proteasome inhibitor, PS-519, has been shown to attenuate leukocyte-endothelial cell interactions. We tested the effects of PS-519 on neutrophil mediated cardiac dysfunction in ischemia/reperfusion. This study examines the effects of PS-519 in a neutrophil dependent isolated perfused rat heart model of ischemia (I) (20 min) and reperfusion (R) (45 min). Administration of PS-519 (0.01, 0.1, 0.3, 1.0 mg/kg) to I/R hearts perfused with PMNs improved coronary flow, and preserved left ventricular developed pressure (LVDP) and +dP/dt max as indices of cardiac contractile function. At 1.0 mg/kg, PS-519 treated hearts exhibited a final LVDP of 98 +/- 3% of initial compared to 52 +/- 8% in I/R hearts receiving only vehicle (P < 0.001). In addition, PS-519 significantly reduced PMN accumulation in the ischemic myocardium from 25.1 +/- 2.1 PMNs/mm(2) in untreated hearts to 7.3 PMNs/mm(2), and attenuated P-selectin surface expression on coronary vascular endothelium from 7.lt0.30/u to 1.4 +/- 0.2% (P < 0.01). These results provide evidence that PS-519 is a potent and effective cardioprotective agent that inhibits P-selectin leukocyte-endothelial cell interactions and preserves cardiac contractile function and coronary perfusion following myocardial ischemia and reperfusion. (C) 1999 Academic Press.