背景:射血分数降低(HFrEF)的心力衰竭是心肌梗死(MI)的主要后果。我们先前已经证明,微粒体前列腺素E合酶-1(mPGES-1)/PGE2途径限制了急性心肌缺血后的再灌注损伤。然而,目前尚不清楚mPGES-1的药理学抑制是否与环氧合酶-2选择性非甾体抗炎药(NSAIDs)相比血栓形成风险较低,影响心肌梗死后的慢性心脏重塑。
方法:小鼠进行左冠状动脉前降支结扎,然后用mPGES-1抑制剂CIII或118,塞来昔布(环氧合酶-2抑制剂)或媒介物进行腹膜内治疗,每天一次,共28天。通过液相色谱串联质谱法测量尿前列腺素代谢产物。
结果:与溶媒或塞来昔布相比,长期给予CIII可改善MI后小鼠的心功能。CIII不影响血栓形成或血压。此外,CIII减少了梗死面积,增大疤痕厚度,胶原蛋白I/III比率降低,降低纤维化相关基因的表达,缺血区毛细血管密度增加。分流到PGI2的尿代谢产物,而不是血栓素B2或PGD2,抑制mPGES-1后与MI后心功能呈正相关。与媒介物或塞来昔布相比,CIII的施用显着增加了尿PGI2/PGE2代谢物的比例。PGI2/PGE2代谢物比值与射血分数呈正相关,分数缩短和疤痕厚度。用118治疗也改善了心脏功能。
结论:抑制mPGES-1可通过增加PGI2/PGE2代谢物比值预防慢性不良心脏重塑,因此代表了MI后HFrEF发展的潜在治疗策略。
Heart failure with reduced ejection fraction (HFrEF) is a major consequence of myocardial infarction (MI). The microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway has been shown to constrain reperfusion injury after acute myocardial ischaemia. However, it is unknown whether pharmacological inhibition of mPGES-1, a target with lower risk of thrombosis compared with selective inhibition of cyclooxygenase-2, affects chronic cardiac remodelling after MI.
Mice were subjected to left anterior descending coronary artery ligation, followed by intraperitoneal treatment with the mPGES-1 inhibitor compound III (CIII) or 118, celecoxib (cyclooxygenase-2 inhibitor) or vehicle, once daily for 28 days. Urinary prostanoid metabolites were measured by liquid chromatography-tandem mass spectrometry.
Chronic administration of CIII improved cardiac function in mice after MI compared with vehicle or celecoxib. CIII did not affect thrombogenesis or blood pressure. In addition, CIII reduced infarct area, augmented scar thickness, decreased collagen I/III ratio, decreased the expression of fibrosis-related genes and increased capillary density in the ischaemic area. Shunting to urinary metabolites of
PGI2 , not thromboxane B2 or PGD2 , after inhibition of mPGES-1 was positively correlated with cardiac function after MI. CIII administration significantly increased urinary
PGI2 /PGE2 metabolite ratio compared to vehicle or celecoxib. The
PGI2 /PGE2 metabolite ratio correlated positively with ejection fraction, fractional shortening and scar thickness. Treatment with 118 also improved cardiac function.
Inhibition of mPGES-1 prevented chronic adverse cardiac remodelling via an augmented
PGI2 /PGE2 metabolite ratio and therefore represents a potential therapeutic strategy for development of HFrEF after MI.