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The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis.

Kowalczyk A, Kleniewska P, Kolodziejczyk M, Skibska B, Goraca A - Arch. Immunol. Ther. Exp. (Warsz.) (2014)

Bottom Line: These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade.ET-1 receptor antagonists may be useful for prevention of various vascular diseases.This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

View Article: PubMed Central - PubMed

Affiliation: Chair of Experimental and Clinical Physiology, Department of Cardiovascular Physiology, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland, akkowalczyk@o2.pl.

ABSTRACT
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

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ETA receptor-mediated VSMC signalling pathways. Activation of the ETA receptor stimulates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4.5-bisphosphate (PIP2). IP3 induces Ca2+ outflow from intracellular stores in sarcoplasmic reticulum (SR). Furthermore, the ETA receptor acts on nonselective plasmalemmal Ca2+ channels causing Ca2+ input from the extracellular space. Consequently, increased concentrations of Ca2+ leads to the contraction of VSMC. The activated ETA receptor also stimulates cell growth. Production of DAG activates protein kinase C (PKC), which is responsible for the mitogenic function of endothelin, and which also induces a Ca2+-independent pathway of VSMC contraction involving calponin phosphorylation. PKC affects gene transcription through activation of the Ras/Raf/MEK/MAPK cascade. MAPK phosphorylates caldesmon, which increases VSMC contraction (Hynynen and Khalil 2006; Khalil 2011; Lima et al. 2011)
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Fig1: ETA receptor-mediated VSMC signalling pathways. Activation of the ETA receptor stimulates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4.5-bisphosphate (PIP2). IP3 induces Ca2+ outflow from intracellular stores in sarcoplasmic reticulum (SR). Furthermore, the ETA receptor acts on nonselective plasmalemmal Ca2+ channels causing Ca2+ input from the extracellular space. Consequently, increased concentrations of Ca2+ leads to the contraction of VSMC. The activated ETA receptor also stimulates cell growth. Production of DAG activates protein kinase C (PKC), which is responsible for the mitogenic function of endothelin, and which also induces a Ca2+-independent pathway of VSMC contraction involving calponin phosphorylation. PKC affects gene transcription through activation of the Ras/Raf/MEK/MAPK cascade. MAPK phosphorylates caldesmon, which increases VSMC contraction (Hynynen and Khalil 2006; Khalil 2011; Lima et al. 2011)

Mentions: Two types of endothelin receptors are found in mammals, ETA and ETB receptors, which belong to the G protein-coupled receptors family. ETA receptors are located mostly in vascular smooth muscle cells (VSMC), where they are responsible for potent vascular contraction (Fig. 1), cell proliferation and a proinflammatory effect. ETB receptors include two subtypes: ETB1, which is expressed on endothelial cells and evokes NO-mediated vasodilation, and ETB2, also present in VSMC, which causes contraction (Hynynen and Khalil 2006; Yanagisawa et al. 1988). Stimulation of ETB1 receptors also results in the release of other vasodilatory factors such as prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor. Furthermore, it is suggested that endothelial ETB receptors take part in ET-1 clearance, but findings are not unequivocal (Hynynen and Khalil 2006; Kawanabe and Nauli 2011; Ohkita et al. 2012).Fig. 1


The role of endothelin-1 and endothelin receptor antagonists in inflammatory response and sepsis.

Kowalczyk A, Kleniewska P, Kolodziejczyk M, Skibska B, Goraca A - Arch. Immunol. Ther. Exp. (Warsz.) (2014)

ETA receptor-mediated VSMC signalling pathways. Activation of the ETA receptor stimulates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4.5-bisphosphate (PIP2). IP3 induces Ca2+ outflow from intracellular stores in sarcoplasmic reticulum (SR). Furthermore, the ETA receptor acts on nonselective plasmalemmal Ca2+ channels causing Ca2+ input from the extracellular space. Consequently, increased concentrations of Ca2+ leads to the contraction of VSMC. The activated ETA receptor also stimulates cell growth. Production of DAG activates protein kinase C (PKC), which is responsible for the mitogenic function of endothelin, and which also induces a Ca2+-independent pathway of VSMC contraction involving calponin phosphorylation. PKC affects gene transcription through activation of the Ras/Raf/MEK/MAPK cascade. MAPK phosphorylates caldesmon, which increases VSMC contraction (Hynynen and Khalil 2006; Khalil 2011; Lima et al. 2011)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4289534&req=5

Fig1: ETA receptor-mediated VSMC signalling pathways. Activation of the ETA receptor stimulates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4.5-bisphosphate (PIP2). IP3 induces Ca2+ outflow from intracellular stores in sarcoplasmic reticulum (SR). Furthermore, the ETA receptor acts on nonselective plasmalemmal Ca2+ channels causing Ca2+ input from the extracellular space. Consequently, increased concentrations of Ca2+ leads to the contraction of VSMC. The activated ETA receptor also stimulates cell growth. Production of DAG activates protein kinase C (PKC), which is responsible for the mitogenic function of endothelin, and which also induces a Ca2+-independent pathway of VSMC contraction involving calponin phosphorylation. PKC affects gene transcription through activation of the Ras/Raf/MEK/MAPK cascade. MAPK phosphorylates caldesmon, which increases VSMC contraction (Hynynen and Khalil 2006; Khalil 2011; Lima et al. 2011)
Mentions: Two types of endothelin receptors are found in mammals, ETA and ETB receptors, which belong to the G protein-coupled receptors family. ETA receptors are located mostly in vascular smooth muscle cells (VSMC), where they are responsible for potent vascular contraction (Fig. 1), cell proliferation and a proinflammatory effect. ETB receptors include two subtypes: ETB1, which is expressed on endothelial cells and evokes NO-mediated vasodilation, and ETB2, also present in VSMC, which causes contraction (Hynynen and Khalil 2006; Yanagisawa et al. 1988). Stimulation of ETB1 receptors also results in the release of other vasodilatory factors such as prostacyclin (PGI2) and endothelium-derived hyperpolarizing factor. Furthermore, it is suggested that endothelial ETB receptors take part in ET-1 clearance, but findings are not unequivocal (Hynynen and Khalil 2006; Kawanabe and Nauli 2011; Ohkita et al. 2012).Fig. 1

Bottom Line: These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade.ET-1 receptor antagonists may be useful for prevention of various vascular diseases.This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

View Article: PubMed Central - PubMed

Affiliation: Chair of Experimental and Clinical Physiology, Department of Cardiovascular Physiology, Medical University of Lodz, Mazowiecka 6/8, 92-215, Lodz, Poland, akkowalczyk@o2.pl.

ABSTRACT
Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, mainly secreted by endothelial cells. It acts through two types of receptors: ETA and ETB. Apart from a vasoconstrictive action, ET-1 causes fibrosis of the vascular cells and stimulates production of reactive oxygen species. It is claimed that ET-1 induces proinflammatory mechanisms, increasing superoxide anion production and cytokine secretion. A recent study has shown that ET-1 is involved in the activation of transcription factors such as NF-κB and expression of proinflammatory cytokines including TNF-α, IL-1, and IL-6. It has been also indicated that during endotoxaemia, the plasma level of ET-1 is increased in various animal species. Some authors indicate a clear correlation between endothelin plasma level and morbidity/mortality rate in septic patients. These pathological effects of ET-1 may be abrogated at least partly by endothelin receptor blockade. ET-1 receptor antagonists may be useful for prevention of various vascular diseases. This review summarises the current knowledge regarding endothelin receptor antagonists and the role of ET-1 in sepsis and inflammation.

Show MeSH
Related in: MedlinePlus