Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury
Genetic disruption of poly (ADP-ribose) synthetase inhibits the expression of P-selectin and intercellular adhesion molecule-1 in myocardial ischemia/reperfusion injury
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DOI：
10.1161/01.res.83.1.85
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发表时间：
1998-07-13
影响因子：
20.1
通讯作者：
Szabó, C
中科院分区：
文献类型：
--
作者：
Zingarelli, B;Salzman, AL;Szabó, C
核酶多(ADP-核糖)合成酶(PARS)在缺血/再灌注损伤和循环休克的发病机制中起重要作用。这项研究的目的是调查PARS活性是否可能调节内皮-中性粒细胞的相互作用。我们提供的证据表明，PARS的基因破坏通过抑制P-选择素和细胞间黏附分子-1(ICAM-1)的表达，从而通过抑制中性粒细胞向受损组织的募集来提供对心肌缺血和再灌注损伤的保护。此外，利用体外研究，我们证明在缺乏PARS功能基因的成纤维细胞中，细胞因子刺激的ICAM-1的表达比来自正常基因的动物的成纤维细胞显著减少，类似地，在培养的人内皮细胞中，氧化或细胞因子依赖性的P-选择素和ICAM-1的表达通过药物抑制PARS而减少。这些结果首次为PARS激活通过调节P-选择素和ICAM-1在缺血和再灌流心肌中的表达而参与中性粒细胞介导的心肌损伤提供了直接证据，也为治疗再灌注损伤提供了新的治疗途径。
The nuclear enzyme poly (ADP-ribose) synthetase (PARS) has been shown to play an important role in the pathogenesis of ischemia/reperfusion injury and circulatory shock. The aim of this study was to investigate whether PARS activity may modulate endothelial-neutrophil interaction. We present evidence that genetic disruption of PARS provides protection against myocardial ischemia and reperfusion injury by inhibiting the expression of P-selectin and intercellular adhesion molecule-1 (ICAM-1) and, consequently, by inhibiting the recruitment of neutrophils into the jeopardized tissue. Furthermore, using in vitro studies, we demonstrate that in fibroblasts lacking a functional gene for PARS, cytokine-stimulated expression of ICAM-1 is significantly reduced compared with fibroblasts from animals with a normal genotype, Similarly, in cultured human endothelial cells, oxidative- or cytokine-dependent expression of P-selectin and ICAM-1 is reduced by pharmacological inhibition of PARS by 3-aminobenzamide. These findings provide the first direct evidence that PARS activation participates in neutrophil-mediated myocardial damage by regulating the expression of P-selectin and ICAM-1 in ischemic and reperfused myocardium, and they also provide the basis for a novel therapeutic approach for the treatment of reperfusion injury.