Endogenously generated arachidonate‐derived ligands for TRPV1 induce cardiac protection in sepsis

Abstract

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.

RvE1 Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction and Enhances Bacterial Clearance

“…Cardiac function was assessed in mice by echocardiography in vivo as reported previously ( 14 , 17 ). At 24 h after CLP, anesthesia was induced with 3% isoflurane and maintained at 0.5–0.7% for the duration of the procedure.…”

The Regulation of Pulmonary Vascular Tone by Neuropeptides and the Implications for Pulmonary Hypertension

“…The complicated mechanism for activation is still being unraveled and great progress has been made since 2013 when breakthrough structural information was first reported ( Yang and Zheng, 2017 ). TRPV1 activation is involved in a variety of cardiovascular pathologies, including the modulation of atherosclerosis ( Li et al, 2014 ; Xiong et al, 2016 ), myogenic tone ( Scotland et al, 2004 ; Bubb et al, 2013 ), systemic arterial pressure ( Bubb et al, 2013 ) and hypertension ( Hao et al, 2011 ), congestive heart failure ( Gao et al, 2014 ; Lang et al, 2015 ), vascular remodeling ( Chen et al, 2010 ), haemorrhagic shock ( Akabori et al, 2007 ) and sepsis ( Chen et al, 2018 ).…”

Vascular KATP channels protect from cardiac dysfunction and preserve cardiac metabolism during endotoxemia

“…The level of cardiac dysfunction in these mice was striking with EF at ~ 20% compared with ~ 70% for WT with an LPS insult. Cardiac function was not adversely affected in WT mice following a low-dose LPS challenge—this was not unexpected as the effects of LPS and even CLP on cardiac function have been shown to be dose and time dependent in mice [ 10 , 17 , 21 , 24 ]. We expected a less severe cardiac phenotype given LPS-treated gKO mice are clearly at a survival disadvantage compared with smKO mice.…”

“…We used 2 models of endotoxemia/sepsis—administration of lipopolysaccharide (LPS, Sigma-Aldrich) [ 17 , 18 ] and cecal slurry (CS) from C57/B6 mice [ 19 ]. LPS was used at a dose of 10 mg/kg (I.P) for the blood pressure and survival studies and was reduced to 2 mg/kg (with 0.1 mg/kg peptidoglycan) for further studies.…”