P2X7 受体拮抗剂 A740003 对急性心肌梗死引起的纤维重塑的抗纤维化作用

IF 3 3区 医学 Q2 PHARMACOLOGY & PHARMACY Saudi Pharmaceutical Journal Pub Date : 2024-05-16 DOI:10.1016/j.jsps.2024.102102
Noura Almusallam , Asma Alonazi , Anfal Bin Dayel , Abdullah Almubarak , Rizwan Ali , Wajd Althakfi , Rehab Ali , Nouf Alrasheed
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引用次数: 0

摘要

急性心肌梗塞(AMI)后纤维化是一种病理生理过程,其特点是促纤维化介质转化生长因子-β(TGF-β)被激活。急性心肌梗死与细胞外三磷酸腺苷(eATP)水平的大幅上升有关,eATP 作用于嘌呤能 P2X7-受体(P2X7-R),引发炎症反应,导致心肌纤维重塑。P2X7-R 与多种心血管疾病有关,但它在心肌纤维化调控中的作用仍不清楚。因此,本研究旨在确定 P2X7-R 拮抗剂 A740003 通过促纤维化 TGF-β1/Smad 信号通路对 AMI 后纤维化的影响,并阐明其作用是否通过调节 GSK-3β 介导。通过手术结扎左前降支冠状动脉诱发急性心肌梗死,然后将动物分为假对照组、心肌梗死未处理组、心肌梗死车辆组和 MI-A740003(50 毫克/千克/天)组,并相应处理七天。结果显示,未经治疗的结扎大鼠的心脏重量/体重比显著增加了 15.1%,肌酸激酶-MB(CK-MB)显著增加了 40%,肌钙蛋白-I 水平显著增加了 25.4%,乳酸脱氢酶显著增加了 47.2%,形态学变化和大量心肌纤维化证实了心肌损伤。心脏纤连蛋白、TGF-β1 和 p-Smad2 蛋白表达也分别上调了 143%、40% 和 8%,表明心脏纤维化。用 A740003 治疗结扎大鼠可改善上述所有参数。总之,A740003 通过阻断 P2X7-R 对急性心肌梗死动物模型的急性心肌梗死后纤维重塑具有潜在的心脏保护作用,这可能是通过下调促纤维化 TGF-β1/Smad 信号通路和恢复 GSK-3β 磷酸化实现的。总之,使用 A740003 治疗可作为一种新的心脏保护策略,以减轻急性心肌梗死后的纤维重塑。
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Antifibrotic effect of the P2X7 receptor antagonist A740003 against acute myocardial infarction-induced fibrotic remodelling

Post-acute myocardial infarction (AMI) fibrosis is a pathophysiologic process characterised by activation of the profibrotic mediator, transforming growth factor-β (TGF-β). AMI is associated with a substantial increase in the levels of extracellular adenosine triphosphate (eATP), which acts on the purinergic P2X7-receptor (P2X7-R) and triggers an inflammatory response that contributes to myocardial fibrotic remodelling. P2X7-R has been implicated in several cardiovascular diseases; however, its role in the regulation of cardiac fibrosis remains unclear. Therefore, the current study aimed to determine the effect of the P2X7-R antagonist, A740003, on post-AMI fibrosis, via the profibrotic TGF-β1/Smad signalling pathway, and elucidate whether its effect is mediated via the modulation of GSK-3β. AMI was induced by surgical ligation of the left anterior descending coronary artery, Thereafter, animals were divided into groups: sham control, MI-untreated, MI-vehicle, and MI-A740003 (50 mg/kg/day) and treated for seven days accordingly. The heart weight/body weight ratio of untreated-ligated rats significantly increased by 15.1 %, creatine kinase‐MB (CK‐MB) significantly increased by 40 %, troponin‐I levels significantly increased by 25.4 %, and lactate dehydrogenase significantly increased by 47.2 %, indicating myocardial damage confirmed by morphological changes and massive cardiac fibrosis. The protein expression of cardiac fibronectin, TGF-β1, and p-Smad2 were also upregulated by 143 %, 40 %, and 8 %, respectively, indicating cardiac fibrosis. The treatment of ligated rats with A740003 led to improvement in all the above-mentioned parameters. Overall, A740003 exhibits potential cardio-protective effects on post-AMI fibrotic remodelling in the animal model of AMI through P2X7-R blockade, possibly by downregulating the profibrotic TGF-β1/Smad signalling pathway and restoring GSK-3β phosphorylation. Altogether, treatment with A740003 could serve as a new cardioprotective strategy to attenuate post-AMI fibrotic remodelling.

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来源期刊
Saudi Pharmaceutical Journal
Saudi Pharmaceutical Journal PHARMACOLOGY & PHARMACY-
CiteScore
6.10
自引率
2.40%
发文量
194
审稿时长
67 days
期刊介绍: The Saudi Pharmaceutical Journal (SPJ) is the official journal of the Saudi Pharmaceutical Society (SPS) publishing high quality clinically oriented submissions which encompass the various disciplines of pharmaceutical sciences and related subjects. SPJ publishes 8 issues per year by the Saudi Pharmaceutical Society, with the cooperation of the College of Pharmacy, King Saud University.
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