阿司匹林可增强脂多糖诱导的15-表-脂氧素A4生成，但会阻断吡格列酮和阿托伐他汀在大鼠心脏中对15-表-脂氧素A4的诱导作用。
Aspirin augments 15-epi-lipoxin A4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A4 in the rat heart.
作者信息
Birnbaum Yochai, Ye Yumei, Lin Yu, Freeberg Sheldon Y, Huang Ming-He, Perez-Polo Jose R, Uretsky Barry F
机构信息
The Division of Cardiology, University of Texas Medical Branch, Galveston, TX 77555-0553, USA.
出版信息
Prostaglandins Other Lipid Mediat. 2007 Feb;83(1-2):89-98. doi: 10.1016/j.prostaglandins.2006.10.003. Epub 2006 Nov 7.
Aspirin (ASA) inhibits cycloxygenase-1 and modifies cycloxygenase-2 (COX2) by acetylation at Ser(530), leading to a shift from production of PGH(2), the precursor of prostaglandin, to 15-R-HETE which is converted by 5-lipoxygenase to 15-epi-lipoxin A(4) (15-epi-LXA4), a potent anti-inflammatory mediator. Both atorvastatin (ATV) and pioglitazone (PIO) increase COX2 expression. ATV activates COX2 by S-nitrosylation at Cys(526) to produce 15-epi-LXA4 and 6-keto-PGF(1alpha) (the stable metabolite of PGI(2)). We assessed the effect of ASA on the myocardial production of 15-epi-LXA4 and PGI(2) after induction by lipopolysaccharide (LPS) or PIO+ATV. Sprague-Dawley rats were pretreated with: control; ASA 10 mg/kg; ASA 50 mg/kg; LPS alone; LPS+ASA 10 mg/kg; LPS+ASA 50 mg/kg; LPS+ASA 200 mg/kg; PIO (10 mg/kg/d)+ATV (10 mg/kg/d); PIO+ATV+ASA 10 mg/kg; PIO+ATV+ASA 50 mg/kg; PIO+ATV+ASA 50 mg/kg+1400 W, a specific iNOS inhibitor; or PIO+ATV+1400 W. ASA alone had no effect on myocardial 15-epi-LXA4. LPS increased 15-epi-LXA4 and 6-keto-PGF(1alpha) levels. ASA (50 mg/kg and 200 mg/kg, but not 10 mg/kg) augmented the LPS effect on 15-epi-LXA4 but attenuated the effect on 6-keto-PGF(1alpha). PIO+ATV increased 15-epi-LXA4 and 6-keto-PGF(1alpha) levels. ASA and 1400 W attenuated the effects of PIO+ATV on 15-epi-LXA4 and 6-keto-PGF(1alpha). However, when both ASA and 1400 W were administered with PIO+ATV, there was a marked increase in 15-epi-LXA4, whereas the production of 6-keto-PGF(1alpha) was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF(1alpha) to 15-epi-LXA4. In contrast, S-nitrosylation by PIO+ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF(1alpha). However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA.
阿司匹林（ASA）抑制环氧化酶-1，并通过对丝氨酸（Ser）530进行乙酰化修饰环氧化酶-2（COX2），导致从前列腺素前体PGH₂的生成转变为15-R-HETE，后者经5-脂氧合酶转化为15-表-脂氧素A₄（15-epi-LXA₄），一种强效抗炎介质。阿托伐他汀（ATV）和吡格列酮（PIO）均可增加COX2表达。ATV通过对半胱氨酸（Cys）526进行S-亚硝基化激活COX2，以生成15-epi-LXA₄和6-酮-前列环素F₁α（PGI₂的稳定代谢产物）。我们评估了ASA对脂多糖（LPS）或PIO + ATV诱导后心肌中15-epi-LXA₄和PGI₂生成的影响。将斯普拉格-道利大鼠进行如下预处理：对照组；ASA 10 mg/kg；ASA 50 mg/kg；单独使用LPS；LPS + ASA 10 mg/kg；LPS + ASA 50 mg/kg；LPS + ASA 200 mg/kg；PIO（10 mg/kg/天）+ ATV（10 mg/kg/天）；PIO + ATV + ASA 10 mg/kg；PIO + ATV + ASA 50 mg/kg；PIO + ATV + ASA 50 mg/kg + 1400W（一种特异性诱导型一氧化氮合酶抑制剂）；或PIO + ATV + 1400W。单独使用ASA对心肌15-epi-LXA₄无影响。LPS可增加15-epi-LXA₄和6-酮-前列环素F₁α水平。ASA（50 mg/kg和200 mg/kg，但不是10 mg/kg）增强了LPS对15-epi-LXA₄的作用，但减弱了对6-酮-前列环素F₁α的作用。PIO + ATV可增加15-epi-LXA₄和6-酮-前列环素F₁α水平。ASA和1400W减弱了PIO + ATV对15-epi-LXA₄和6-酮-前列环素F₁α的作用。然而，当ASA和1400W与PIO + ATV同时给药时，15-epi-LXA₄显著增加，而6-酮-前列环素F₁α的生成则减弱。总之，ASA对COX2的乙酰化作用使该酶从生成6-酮-前列环素F₁α转变为生成15-epi-LXA₄。相比之下，PIO + ASA的S-亚硝基化作用增强了15-epi-LXA₄和6-酮-前列环素F₁α两者的生成。然而，当COX2同时发生乙酰化和S-亚硝基化时，它会失活。我们提示他汀类药物、噻唑烷二酮类药物和高剂量ASA之间可能存在不良相互作用。
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