抑制微粒体 PGE 合酶-1 通过增加 PGI 来降低人血管张力：一种比 COX-2 抑制更安全的选择。
Inhibition of microsomal PGE synthase-1 reduces human vascular tone by increasing PGI : a safer alternative to COX-2 inhibition.
机构信息
INSERM U1148, Paris, France.
Faculty of Pharmacy, Department of Pharmacology, Istanbul University, Istanbul, Turkey.
出版信息
Br J Pharmacol. 2017 Nov;174(22):4087-4098. doi: 10.1111/bph.13939. Epub 2017 Aug 11.
BACKGROUND AND PURPOSE
The side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE from COX-derived PGH . This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels.
EXPERIMENTAL APPROACH
The vascular tone and prostanoid release from internal mammary artery (IMA) and saphenous vein (SV) incubated for 30 min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions.
KEY RESULTS
In inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE and PGI were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenaline-induced contractions in both vessels. This effect was reversed by an IP (PGI receptor) antagonist but not modified by NOS inhibition. Moreover, PGI release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE release.
CONCLUSIONS AND IMPLICATIONS
In contrast to COX-2 inhibition, inhibition of mPGES-1 reduced vasoconstriction by increasing PGI synthesis. Targeting mPGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors.
LINKED ARTICLES
This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
背景与目的
环氧化酶-2（COX-2）抑制剂对心血管系统的副作用可能与前列腺素（PG）I 合成减少有关。微粒体 PGE 合酶-1（mPGES-1）催化 COX 衍生的 PGH 转化为 PGE。这种酶在炎症条件下被诱导，是新型抗炎药物的一个有吸引力的靶点。然而，目前尚不清楚 mPGES-1 抑制剂是否可以没有心血管副作用。本研究旨在比较 mPGES-1 和 COX-2 抑制剂在人血管中的血管张力作用。
实验方法
在正常和炎症条件下，用 mPGES-1 或 COX-2 抑制剂孵育 30 分钟后，检测内乳动脉（IMA）和隐静脉（SV）的血管张力和前列腺素释放。
主要结果
在炎症条件下，mPGES-1 和 COX-2 蛋白表达增加，PGI 和 PGE 水平升高。COX-2 和 NOS 抑制剂增加了 IMA 中去甲肾上腺素诱导的血管收缩，而在 SV 中没有观察到这种作用。有趣的是，mPGES-1 抑制剂显著降低了两种血管中去甲肾上腺素诱导的收缩（30-40%）。这种作用被 IP（PGI 受体）拮抗剂逆转，但不受 NOS 抑制的影响。此外，mPGES-1 抑制剂增加了 PGI 释放，而 COX-2 抑制剂降低了 PGE 释放，同时两者都降低了 PGE 释放。
结论与意义
与 COX-2 抑制不同，mPGES-1 抑制通过增加 PGI 合成减少血管收缩。与 COX-2 抑制剂相比，靶向 mPGES-1 可能降低心血管副作用的风险。
相关文章
本文是一个以“靶向炎症以降低心血管疾病风险”为主题的专题的一部分。要查看本专题中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc 和 http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc。
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