Effects of selective inhibition of cytochrome P-450 omega-hydroxylases and ischemic preconditioning in myocardial protection.
Effects of selective inhibition of cytochrome P-450 omega-hydroxylases and ischemic preconditioning in myocardial protection.
复制标题
选择性抑制细胞色素 P-450 omega-羟化酶和缺血预处理对心肌保护的影响。
DOI：
10.1152/ajpheart.00918.2005
复制
发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Gross,GarrettJ
中科院分区：
文献类型：
--
作者：
Nithipatikom,Kasem;Endsley,MichaelP;Moore,JeannineM;Isbell,MarilynA;Falck,JohnR;Campbell,WilliamB;Gross,GarrettJ
CytochromeP-450 (CYP) ω-羟化酶及其花生四烯酸（AA）代谢物20-羟基二碳四烯酸（20-HETE）对犬心脏缺血再灌注损伤有不利影响，抑制CYP ω-羟化酶可显著降低心肌梗死面积占危险面积的百分比（IS/AAR, %）。在这项研究中，我们证明了一种特异性的CYP ω-羟化酶抑制剂n -甲基磺酰基-12,12-二溴十二烷-11-氨基酰胺（DDMS）与对照组相比，在缺血-再灌注期间显著减少20-HETE的产生，并减少心肌梗死面积[19.5±1.0%（对照组），9.6±1.5% (0.40 mg/kg DDMS), 4.0±2.0% (0.81 mg/kg DDMS)，P< 0.01]。此外，与对照组相比，20-羟基糖-6(Z),15(Z)-二烯酸（20-HEDE，一种假定的20-HEDE拮抗剂）显著降低心肌梗死面积[10.3±1.3% （0.032 mg/kg 20-HEDE）和5.9±1.9% (0.064 mg/kg 20-HEDE)，P< 0.05]。我们进一步证明，5分钟的缺血预处理（IPC）减少梗死面积的程度与高剂量DDMS和20-HEDE相似，并且与IPC同时给予的高剂量DDMS增加了梗死面积的减少[9.9±2.8% （IPC）至2.5±1.4% (0.81 mg/kg DDMS)，P< 0.05]，其程度大于单独使用任何一种治疗。这些结果提示内源性CYP ω-羟化酶及其产物20-HETE在犬心肌损伤中具有重要的负作用。此外，本研究首次证明了IPC的作用和抑制CYP ω-羟化酶合成（DDMS）或其作用（20-HEDE）可能在保护犬心脏缺血再灌注损伤方面具有加性作用。
CytochromeP-450 (CYP) ω-hydroxylases and their arachidonic acid (AA) metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE), produce a detrimental effect on ischemia-reperfusion injury in canine hearts, and the inhibition of CYP ω-hydroxylases markedly reduces myocardial infarct size expressed as a percentage of the area at risk (IS/AAR, %). In this study, we demonstrated that a specific CYP ω-hydroxylase inhibitor,N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), markedly reduced 20-HETE production during ischemia-reperfusion and reduced myocardial infarct size compared with control [19.5 ± 1.0% (control), 9.6 ± 1.5% (0.40 mg/kg DDMS), 4.0 ± 2.0% (0.81 mg/kg DDMS),P< 0.01]. In addition, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE, a putative 20-HETE antagonist) significantly reduced myocardial infarct size from control [10.3 ± 1.3% (0.032 mg/kg 20-HEDE) and 5.9 ± 1.9% (0.064 mg/kg 20-HEDE),P< 0.05]. We further demonstrated that one 5-min period of ischemic preconditioning (IPC) reduced infarct size to a similar extent as that observed with the high doses of DDMS and 20-HEDE, and the higher dose of DDMS given simultaneously with IPC augmented the infarct size reduction [9.9 ± 2.8% (IPC) to 2.5 ± 1.4% (0.81 mg/kg DDMS),P< 0.05] to a greater degree than that observed with either treatment alone. These results suggest an important negative role for endogenous CYP ω-hydroxylases and their product, 20-HETE, to exacerbate myocardial injury in canine myocardium. Furthermore, for the first time, this study demonstrates that the effect of IPC and the inhibition of CYP ω-hydroxylase synthesis (DDMS) or its actions (20-HEDE) may have additive effects in protecting the canine heart from ischemia-reperfusion injury.