Endothelin-1 (1–31): From chymase-dependent synthesis to cardiovascular pathologies

D’Orléans-Juste, Pedro; Houde, Mathieu; Rae, Giles A.; Bkaily, Ghassan; Simard, Elie

doi:10.1016/j.vph.2008.06.007

Cited by 31 publications

(20 citation statements)

References 165 publications

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“…S1), we focused on the link between chymase and three different signalling pathways that are known to be potentially involved in both PH and PF pathologies, such as ET-1, TGF-β and MMP-2 [18-23, 25, 26, 43]. MC chymase converts big-ET-1 into 31 amino-acid ET-1(1-31), which can be further processed into ET-1 (1-21) by neutral NEP, suggesting the role of this MC mediator in maturation of ET-1 [5,[8][9][10]. In this context, the ET-1 system is indeed implicated as an important culprit in PH and lung fibrosis [19][20][21].…”

Section: Discussionmentioning

confidence: 99%

“…Controversially, it has to be taken into consideration the fact that chymase may even exert ET-1 degrading activities [10,45]. Altered TGF-β signalling plays a role in development of PH and PF [5,18,24,25,39,43,46].…”

Section: Discussionmentioning

confidence: 99%

“…MCs produce different mediators involved in inflammatory response [4]. Among MC mediators, the chymase may be of particular interest in the context of PH and IPF, owing to its function in activation and processing of transforming growth factor (TGF)-β, endothelin (ET)-1, angiotensin II, interleukins (IL)-1 and IL-18, matrix metalloproteinases (MMP)-2 and 9, and potential involvement in collagen synthesis [5][6][7][8][9][10][11][12][13][14][15][16]. Following this knowledge, it is worth noting that most of the above mentioned molecular mediators/ signalling pathways are suggested to be important culprits in PH and IPF pathologies, thus indicating the potential link between chymase and these diseases [5,[17][18][19][20][21][22][23][24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

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Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

et al. 2015

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Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form. @ERSpublications Chymase plays an important role in pathology of pulmonary hypertension associated with lung fibrosis

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

et al. 2015

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“…Among those isoforms, studies on the role of chymase in the synthesis of Ang-II suggest that mouse mast cell protease 4 (mMCP-4) is the murine isoform having the most similar proteolytic activity to that of human chymase (Caughey, 2007;Andersson et al, 2008;D'Orléans-Juste et al, 2008). Whether mMCP-4 is also involved in the generation of ET-1 from its precursor Big-ET-1 has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Houde

Jamain

Labonté

et al. 2013

J Pharmacol Exp Ther

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The serine protease chymase has been reported to generate intracardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin-1 (ET-1), ET-1 (1-31) from Big-ET-1. Although humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model. Basal mean arterial pressure did not differ between wild-type (WT) and mMCP-4(2/2) mice. Systemic administration of Big-ET-1 triggered pressor responses and increased blood levels of immunoreactive (IR) ET-1 (1-31) and ET-1 that were reduced by more than 50% in mMCP-4 knockout (2/2) mice compared with WT controls.Residual responses to Big-ET-1 in mMCP-4(2/2) mice were insensitive to the enkephalinase/neutral endopeptidase inhibitor thiorphan and the specific chymase inhibitor TY-51469 {2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl]thiazole-4-carboxylic acid}. Soluble fractions from the lungs, left cardiac ventricle, aorta, and kidneys of WT but not mMCP-4(2/2) mice generated ET-1 (1-31) from exogenous Big-ET-1 in a TY-51469-sensitive fashion as detected by high-performance liquid chromatography/ matrix-assisted laser desorption/ionization-mass spectrometry. Finally, pulmonary endogenous levels of IR-ET-1 were reduced by more than 40% in tissues derived from mMCP-4(2/2) mice compared with WT mice. Our results show that mMCP-4 plays a pivotal role in the dynamic conversion of systemic Big-ET-1 to ET-1 in the mouse model.

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“…They will be referred to excellent reviews on O-GlcNAcylation (54,55,63,84,90,110,167,169,177). Detailed information on ET peptides, ET receptors, ET signaling, models for the study of ET in disease conditions, and development and therapeutic use of ET A /ET B receptor antagonists can be found on excellent and more comprehensive reviews on these specific topics (6,8,11,12,30,31,34,37,67,79,81,115,122,131,141,142,154,160,166).…”

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confidence: 99%

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

Lima

Giachini

Hardy

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Glycosylation with Olinked ␤-N-acetylglucosamine (O-GlcNAc) or O-GlcNAcylation on serine and threonine residues of nuclear and cytoplasmic proteins is a posttranslational modification that alters the function of numerous proteins important in vascular function, including kinases, phosphatases, transcription factors, and cytoskeletal proteins. O-GlcNAcylation is an innovative way to think about vascular signaling events both in physiological conditions and in disease states. This posttranslational modification interferes with vascular processes, mainly vascular reactivity, in conditions where endothelin-1 (ET-1) levels are augmented (e.g. salt-sensitive hypertension, ischemia/reperfusion, and stroke). ET-1 plays a crucial role in the vascular function of most organ systems, both in physiological and pathophysiological conditions. Recognition of ET-1 by the ET A and ETB receptors activates intracellular signaling pathways and cascades that result in rapid and long-term alterations in vascular activity and function. Components of these ET-1-activated signaling pathways (e.g., mitogen-activated protein kinases, protein kinase C, RhoA/Rho kinase) are also targets for O-GlcNAcylation. Recent experimental evidence suggests that ET-1 directly activates O-GlcNAcylation, and this posttranslational modification mediates important vascular effects of the peptide. This review focuses on ET-1-activated signaling pathways that can be modified by O-GlcNAcylation. A brief description of the O-GlcNAcylation biology is presented, and its role on vascular function is addressed. ET-1-induced O-GlcNAcylation and its implications for vascular function are then discussed. Finally, the interplay between O-GlcNAcylation and O-phosphorylation is addressed. endothelin receptor; vascular signaling; O-GlcNAc modification GLYCOSYLATION IS THE SITE-specific enzymatic addition of saccharides to proteins and lipids. There are many types of glycosylation, but great interest has been directed to O-GlcNAcylation, or glycosylation with O-linked ␤-N-acetylglucosamine or ␤-Olinked 2-acetamido-2-deoxy-D-glycopyranose (54,55,169). In this unusual form of protein glycosylation, a single sugar [␤-N-acetylglucosamine (O-GlcNAc)] is added to serine and threonine residues of nuclear or cytoplasmic proteins (54,55,169).Considering that almost every functional class of proteins is subject to O-GlcNAcylation (55, 177), this specific posttranslational modification has been implicated in several biological functions, including transcription or translation, stress responses, and energy metabolism. Proteins with an important role in vascular function are also targets for O-GlcNAcylation. Examples include endothelial nitric oxide (NO) synthase (eNOS), sarcoplasmic reticulum calcium (Ca 2ϩ )-ATPase (SERCA), phospholipase C (PLC), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), and proteins involved in cytoskeleton regulation and microtubule assembly (22,55,177), indicating that this posttranslational modification may play an important role in vascular (...

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Endothelin-1 (1–31): From chymase-dependent synthesis to cardiovascular pathologies

Cited by 31 publications

References 165 publications

Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

O-GlcNAcylation: a novel pathway contributing to the effects of endothelin in the vasculature

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