Upregulation of the maresin pathway and PGE2 metabolism in the failing human left ventricle

IF 3.9 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular and cell biology of lipids Pub Date : 2025-06-12 DOI:10.1016/j.bbalip.2025.159645

Amel Bouhadoun , Hasanga D. Manikpurage , Gaelle Merheb , Alexandre Boutigny , Marc Dubourdeau , Vincent Baillif , Catherine Deschildre , Marylou Para , Aurélie Sannier , Lydia Deschamps , Benjamin Richard , Benoît Ho-Tin-Noé , Jean-Baptiste Michel , Marianne Abifadel , Jean-Etienne Fabre , Valérie Urbach , Dan Longrois , Xavier Norel

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引用次数: 0

Abstract

Chronic inflammation is involved in the pathogenesis of heart failure (HF), with cardiac remodeling and fibrosis resulting from sustained myofibroblasts activation. This is due to an imbalance between pro-inflammatory and pro-resolving mediators including specialized pro-resolving lipid mediators (SPM). This study aimed to explore the SPM pathway and its crosstalks with other pathways in human left ventricle (LV) samples from HF-patients and non-HF donors or in ex-vivo cultured cardiac fibroblasts.

The SPM content was measured in LV samples from HF-patients and donors. Resolvin D5 (RvD5) and maresin-1 (MaR1) were the most abundant SPM and with similar levels between both groups, at baseline. Following exposure to exogenous DHA or EPA, SPM levels increased in both groups but MaR1 and 7(S)-MaR1 have shown a significantly higher increase in ex-vivo LV samples from HF-patients compared to donors. Furthermore, we found a higher expression of the related enzymes (lipoxygenases, LOXs): 15-LOX-1, 15-LOX-2 and 12-LOX in HF-patients LV in vitro samples. Finally, the MaR1 receptor (LGR6) expression was also increased in these LV samples from HF-patients compared to donors. In addition, we investigated the role of SPM on COX-2/mPGES-1/prostaglandin E₂ (PGE₂) pathway previously described as cardioprotective in HF. In cardiac fibroblasts from HF-patients, exposed to inflammatory conditions, RvD1 and MaR1 increased PGE₂ biosynthesis while RvD5 decreased it.

Taken together, our data show an enhanced MaR1 biosynthesis and functional pathway in the heart from HF-patients. Furthermore, in cultured cardiac fibroblasts, MaR1 increased the PGE₂ concentration levels. These data highlighted novel aspects of inflammation regulation in HF physiopathology.

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衰竭的人左心室maresin通路和PGE2代谢的上调。

慢性炎症参与心力衰竭（HF）的发病机制，由持续的肌成纤维细胞激活引起心脏重塑和纤维化。这是由于促炎和促溶解介质之间的不平衡，包括专门的促溶解脂质介质（SPM）。本研究旨在探讨hf患者和非hf供体左心室（LV）样本或离体培养的心脏成纤维细胞中SPM通路及其与其他通路的串扰。在hf患者和供者的LV样品中测量SPM含量。Resolvin D5 （RvD5）和marsin -1 （MaR1）是最丰富的SPM，在基线时两组之间的水平相似。暴露于外源性DHA或EPA后，两组的SPM水平均升高，但与供体相比，来自hf患者的离体LV样本中MaR1和7(S)-MaR1的升高明显更高。此外，我们发现相关酶（脂氧合酶，LOXs）： 15-LOX-1, 15-LOX-2和12-LOX在hf患者LV体外样品中表达较高。最后，与供体相比，来自hf患者的LV样本中的MaR1受体（LGR6）表达也有所增加。此外，我们研究了SPM对COX-2/mPGES-1/前列腺素E2 （PGE2）途径的作用，该途径之前被认为是HF的心脏保护作用。在hf患者的心脏成纤维细胞中，暴露于炎症条件下，RvD1和MaR1增加了PGE2的生物合成，而RvD5则降低了PGE2的生物合成。综上所述，我们的数据显示hf患者心脏中MaR1的生物合成和功能途径增强。此外，在培养的心脏成纤维细胞中，MaR1增加了PGE2的浓度水平。这些数据突出了心衰生理病理中炎症调节的新方面。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochimica et biophysica acta. Molecular and cell biology of lipids 生物-生化与分子生物学

CiteScore

11.00

自引率

2.10%

发文量

109

审稿时长

53 days

期刊介绍： BBA Molecular and Cell Biology of Lipids publishes papers on original research dealing with novel aspects of molecular genetics related to the lipidome, the biosynthesis of lipids, the role of lipids in cells and whole organisms, the regulation of lipid metabolism and function, and lipidomics in all organisms. Manuscripts should significantly advance the understanding of the molecular mechanisms underlying biological processes in which lipids are involved. Papers detailing novel methodology must report significant biochemical, molecular, or functional insight in the area of lipids.