William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
FASEB J. 2018 Jul;32(7):3816-3831. doi: 10.1096/fj.201701303R. Epub 2018 Feb 20.
The severity of cardiac dysfunction predicts mortality in sepsis. Activation of transient receptor potential vanilloid receptor type (TRPV)-1, a predominantly neuronal nonselective cation channel, has been shown to improve outcome in sepsis and endotoxemia. However, the role of TRPV1 and the identity of its endogenous ligands in the cardiac dysfunction caused by sepsis and endotoxemia are unknown. Using TRPV1 and TRPV1 mice, we showed that endogenous activation of cardiac TRPV1 during sepsis is key to limiting the ensuing cardiac dysfunction. Use of liquid chromatography-tandem mass spectrometry lipid analysis and selective inhibitors of arachidonic metabolism suggest that the arachidonate-derived TRPV1 activator, 20-hydroxyeicosateraenoic acid (20-HETE), underlies a substantial component of TRPV1-mediated cardioprotection in sepsis. Moreover, using selective antagonists for neuropeptide receptors, we show that this effect of TRPV1 relates to the activity of neuronally released cardiac calcitonin gene-related peptide (CGRP) and that, accordingly, administration of CGRP can rescue cardiac dysfunction in severe endotoxemia. In sum activation of TRPV1 by 20-HETE leads to the release of CGRP, which protects the heart against the cardiac dysfunction in endotoxemia and identifies both TRPV1 and CGRP receptors as potential therapeutic targets in endotoxemia.-Chen, J., Hamers, A. J. P., Finsterbusch, M., Massimo, G., Zafar, M., Corder, R., Colas, R. A., Dalli, J., Thiemermann, C., Ahluwalia, A. Endogenously generated arachidonate-derived ligands for TRPV1 induce cardiac protection in sepsis.
心脏功能障碍的严重程度预测脓毒症的死亡率。已经表明，瞬时受体电位香草酸受体 1（TRPV1）的激活，一种主要的神经元非选择性阳离子通道，可改善脓毒症和内毒素血症的预后。然而，TRPV1 的作用及其内源性配体在脓毒症和内毒素血症引起的心脏功能障碍中的作用尚不清楚。使用 TRPV1 和 TRPV1 小鼠，我们表明，脓毒症期间心脏 TRPV1 的内源性激活是限制随后心脏功能障碍的关键。使用液相色谱-串联质谱脂质分析和花生四烯酸代谢的选择性抑制剂表明，花生四烯酸衍生的 TRPV1 激活剂 20-羟基二十碳四烯酸（20-HETE）是 TRPV1 介导的脓毒症心脏保护的重要组成部分。此外，使用神经肽受体的选择性拮抗剂，我们表明 TRPV1 的这种作用与神经元释放的降钙素基因相关肽（CGRP）的活性有关，因此，CGRP 的给药可以挽救严重内毒素血症中的心脏功能障碍。总之，20-HETE 通过 TRPV1 的激活导致 CGRP 的释放，CGRP 保护心脏免受内毒素血症中的心脏功能障碍，并且鉴定 TRPV1 和 CGRP 受体作为内毒素血症中的潜在治疗靶点。-Chen，J.，Hamers，A. J. P.，Finsterbusch，M.，Massimo，G.，Zafar，M.，Corder，R.，Colas，R. A.，Dalli，J.，Thiemermann，C.，Ahluwalia，A. 内源性生成的花生四烯酸衍生的 TRPV1 配体在脓毒症中诱导心脏保护。
