Arginase inhibition mediates cardioprotection during ischaemia-reperfusion
Arginase inhibition mediates cardioprotection during ischaemia-reperfusion
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DOI：
10.1093/cvr/cvp303
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发表时间：
2010-01-01
影响因子：
10.8
通讯作者：
Pernow, John
中科院分区：
文献类型：
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作者：
Jung, Christian;Gonon, Adrian T.;Pernow, John
一氧化氮（NO）对心血管系统的完整性和预防缺血性心脏病至关重要。精氨酸酶在缺血再灌注（IR）过程中上调，该酶可能与NO合酶（NOS）竞争精氨酸。本研究调查是否抑制心肌IR损伤的保护，以及这种效果是否耦合到增加NO bioavailability.Methods和结果Sprague-Dawley大鼠进行30分钟的冠状动脉结扎，然后2小时的再灌注。缺血前15 min静脉注射生理盐水或NOS抑制剂N-ω-羟基-去甲-L-精氨酸（nor-NOHA），同时静脉注射或不注射NO清除剂羧基-2-苯基-4，4，5，5-四甲基-咪唑啉-1-氧基-3-氧化物（cPTIO）或NOS抑制剂N-G-单甲基-L-精氨酸（L-NMMA）。对照组的梗死面积为危险区域的79 ± 4%。Nor-NOHA治疗使梗死面积减少至39 ± 7%（P < 0.001）。给予cPTIO或L-NMMA完全消除了nor-NOHA的保护作用。心肌缺血时，心肌细胞中的ATP酶I表达明显增加（P < 0.05）。Nor-NOHA治疗导致血浆亚硝酸盐水平升高（P < 0.05），瓜氨酸/鸟氨酸比值增加10倍（P < 0.001），表明精氨酸利用向NOS转移。结论抑制精氨酸酶通过将精氨酸利用从精氨酸酶向NOS转移，依赖于NOS活性和NO的生物利用度来保护心肌梗死。这些结果表明，靶向的心肌酶是一个有前途的未来的治疗策略，对心肌IR损伤的保护。
Aims Nitric oxide (NO) is vital for the integrity of the cardiovascular system and protection against ischaemic heart disease. Arginase is up-regulated during ischaemia-reperfusion (IR) and this enzyme might compete with NO synthase (NOS) for arginine. The present study investigated whether arginase blockade protects from myocardial IR injury and whether such an effect is coupled to increased NO bioavailability.Methods and results Sprague-Dawley rats were subjected to 30 min of coronary artery ligation, followed by 2 h of reperfusion. The animals were given either saline, or the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA) with or without the NO scavenger carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (cPTIO) or the NOS inhibitor N-G-monomethyl-L-arginine (L-NMMA) iv 15 min before ischaemia. The infarct size was 79 +/- 4% of the area at risk in the control group. Nor-NOHA treatment reduced the infarct size to 39 +/- 7% (P < 0.001). Administration of cPTIO or L-NMMA completely abolished the protective effect of nor-NOHA. Expression of arginase I was significantly (P < 0.05) increased in ischaemic myocardium. Nor-NOHA treatment resulted in higher plasma levels of nitrite (P < 0.05) and a 10-fold increase in the citrulline/ornithine ratio (P < 0.001), indicating a shift in arginine utilization towards NOS.Conclusion Inhibition of arginase protects from myocardial infarction by a mechanism that is dependent on NOS activity and bioavailability of NO by shifting arginine utilization from arginase towards NOS. These findings suggest that targeting of arginase is a promising future therapeutic strategy for protection against myocardial IR injury.