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Fabik J, Psutkova V, Machon O. The Mandibular and Hyoid Arches-From Molecular Patterning to Shaping Bone and Cartilage. Int J Mol Sci 2021; 22:7529. [PMID: 34299147 PMCID: PMC8303155 DOI: 10.3390/ijms22147529] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/02/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
The mandibular and hyoid arches collectively make up the facial skeleton, also known as the viscerocranium. Although all three germ layers come together to assemble the pharyngeal arches, the majority of tissue within viscerocranial skeletal components differentiates from the neural crest. Since nearly one third of all birth defects in humans affect the craniofacial region, it is important to understand how signalling pathways and transcription factors govern the embryogenesis and skeletogenesis of the viscerocranium. This review focuses on mouse and zebrafish models of craniofacial development. We highlight gene regulatory networks directing the patterning and osteochondrogenesis of the mandibular and hyoid arches that are actually conserved among all gnathostomes. The first part of this review describes the anatomy and development of mandibular and hyoid arches in both species. The second part analyses cell signalling and transcription factors that ensure the specificity of individual structures along the anatomical axes. The third part discusses the genes and molecules that control the formation of bone and cartilage within mandibular and hyoid arches and how dysregulation of molecular signalling influences the development of skeletal components of the viscerocranium. In conclusion, we notice that mandibular malformations in humans and mice often co-occur with hyoid malformations and pinpoint the similar molecular machinery controlling the development of mandibular and hyoid arches.
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Affiliation(s)
- Jaroslav Fabik
- Department of Developmental Biology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.F.); (V.P.)
- Department of Cell Biology, Faculty of Science, Charles University, 12800 Prague, Czech Republic
| | - Viktorie Psutkova
- Department of Developmental Biology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.F.); (V.P.)
- Department of Cell Biology, Faculty of Science, Charles University, 12800 Prague, Czech Republic
| | - Ondrej Machon
- Department of Developmental Biology, Institute of Experimental Medicine of the Czech Academy of Sciences, 14220 Prague, Czech Republic; (J.F.); (V.P.)
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2
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Dash S, Trainor PA. The development, patterning and evolution of neural crest cell differentiation into cartilage and bone. Bone 2020; 137:115409. [PMID: 32417535 DOI: 10.1016/j.bone.2020.115409] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 05/04/2020] [Indexed: 12/12/2022]
Abstract
Neural crest cells are a vertebrate-specific migratory, multipotent cell population that give rise to a diverse array of cells and tissues during development. Cranial neural crest cells, in particular, generate cartilage, bone, tendons and connective tissue in the head and face as well as neurons, glia and melanocytes. In this review, we focus on the chondrogenic and osteogenic potential of cranial neural crest cells and discuss the roles of Sox9, Runx2 and Msx1/2 transcription factors and WNT, FGF and TGFβ signaling pathways in regulating neural crest cell differentiation into cartilage and bone. We also describe cranioskeletal defects and disorders arising from gain or loss-of-function of genes that are required for patterning and differentiation of cranial neural crest cells. Finally, we discuss the evolution of skeletogenic potential in neural crest cells and their function as a conduit for intraspecies and interspecies variation, and the evolution of craniofacial novelties.
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Affiliation(s)
- Soma Dash
- Stowers Institute for Medical Research, Kansas City, MO, USA
| | - Paul A Trainor
- Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
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3
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Contrepois K, Wu S, Moneghetti KJ, Hornburg D, Ahadi S, Tsai MS, Metwally AA, Wei E, Lee-McMullen B, Quijada JV, Chen S, Christle JW, Ellenberger M, Balliu B, Taylor S, Durrant MG, Knowles DA, Choudhry H, Ashland M, Bahmani A, Enslen B, Amsallem M, Kobayashi Y, Avina M, Perelman D, Schüssler-Fiorenza Rose SM, Zhou W, Ashley EA, Montgomery SB, Chaib H, Haddad F, Snyder MP. Molecular Choreography of Acute Exercise. Cell 2020; 181:1112-1130.e16. [PMID: 32470399 PMCID: PMC7299174 DOI: 10.1016/j.cell.2020.04.043] [Citation(s) in RCA: 266] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 12/10/2019] [Accepted: 04/21/2020] [Indexed: 02/07/2023]
Abstract
Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.
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Affiliation(s)
- Kévin Contrepois
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
| | - Si Wu
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Kegan J Moneghetti
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, St. Vincent's Hospital, University of Melbourne, Melbourne, VIC, Australia; Stanford Sports Cardiology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Daniel Hornburg
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Sara Ahadi
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Ming-Shian Tsai
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Ahmed A Metwally
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Eric Wei
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Jeniffer V Quijada
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Songjie Chen
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Jeffrey W Christle
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Sports Cardiology, Department of Medicine, Stanford University, Stanford, CA, USA
| | - Mathew Ellenberger
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Brunilda Balliu
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Shalina Taylor
- Pediatrics Department, Stanford University School of Medicine, Stanford, CA, USA
| | - Matthew G Durrant
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - David A Knowles
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Radiology, Stanford University, Stanford, CA, USA
| | - Hani Choudhry
- Department of Biochemistry, Faculty of Science, Cancer and Mutagenesis Unit, King Fahd Center for Medical Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Melanie Ashland
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Amir Bahmani
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Brooke Enslen
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Myriam Amsallem
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Yukari Kobayashi
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Monika Avina
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Dalia Perelman
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | | | - Wenyu Zhou
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Euan A Ashley
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA
| | - Stephen B Montgomery
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University, Stanford, CA, USA
| | - Hassan Chaib
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA
| | - Francois Haddad
- Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
| | - Michael P Snyder
- Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
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4
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Delgado NTB, Rouver WN, Dos Santos RL. Protective Effects of Pomegranate in Endothelial Dysfunction. Curr Pharm Des 2020; 26:3684-3699. [PMID: 32250215 DOI: 10.2174/1381612826666200406152147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 03/10/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Punica granatum L. is an infructescence native of occidental Asia and Mediterranean Europe, popularly referred to as pomegranate. It has been used in ethnomedicine for several applications, including the treatment of obesity, inflammation, diabetes, and the regulation of blood lipid parameters. Thus, pomegranate has been linked to the treatment of cardiovascular diseases that have endothelial dysfunction as a common factor acting mainly against oxidative stress due to its high polyphenol content. Its biocomponents have antihypertensive, antiatherogenic, antihyperglycemic, and anti-inflammatory properties, which promote cardiovascular protection through the improvement of endothelial function. METHODS Different electronic databases were searched in a non-systematic way to uncover the literature of interest. CONCLUSION This review article presents updated information on the role of pomegranate in the context of endothelial dysfunction and cardiovascular diseases. We have shown that pomegranate, or rather its components (e.g., tannins, flavonoids, phytoestrogens, anthocyanins, alkaloids, etc.), have beneficial effects on the cardiovascular system, improving parameters such as oxidative stress and the enzymatic antioxidant system, reducing reactive oxygen species formation and acting in an anti-inflammatory way. Thus, this review may contribute to a better understanding of pomegranate's beneficial actions on endothelial function and possibly to the development of strategies associated with conventional treatments of cardiovascular diseases.
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Affiliation(s)
- Nathalie T B Delgado
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil
| | - Wender N Rouver
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil
| | - Roger L Dos Santos
- Department of Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil
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5
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Nakamura A, Kajitani S, Sato K, Kanazawa M, Kondo M, Endo H, Nozaki E. Decline of popliteal artery flow-mediated dilation with aging and possible involvement of asymmetric dimethylarginine in healthy men. J Med Ultrason (2001) 2019; 46:503-511. [PMID: 31011935 PMCID: PMC6765476 DOI: 10.1007/s10396-019-00946-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 04/05/2019] [Indexed: 12/17/2022]
Abstract
Purpose We examined the influences of age and gender on flow-mediated endothelial function and the involvement of the competitive inhibition of l-arginine in endothelial function. Methods We measured brachial and popliteal flow-mediated vasodilation (FMD) responses, nitrate/nitrite (NOx) concentrations, and plasma levels of asymmetric dimethylarginine (ADMA) in four healthy, nonsmoking groups: young men (mean 26 ± 2 years, n = 17), middle-aged men (mean 50 ± 3 years, n = 19), young women (mean 27 ± 2 years, n = 16), and middle-aged women (mean 51 ± 2 years, n = 18). Results In young men, we found no significant differences between brachial and popliteal artery FMDs (10.6 ± 1.5 vs 8.7 ± 1.6%, p = 0.06). However, the popliteal artery FMD was significantly lower than the brachial artery FMD in middle-aged men (11.4 ± 1.5 vs 6.4 ± 1.0%, p < 0.001). In women, we found no significant differences between brachial and popliteal artery FMDs in young and middle-aged individuals (young, p = 0.17; middle-aged, p = 0.08). Popliteal artery FMD correlated with plasma NOx and ADMA levels as well as with the NOx/ADMA ratio in men but not in women (r = 0.485, − 0.544, and 0.672, respectively). Conclusion We concluded that a decrease in flow-mediated endothelial function in arteries of the lower extremities was evident in healthy middle-aged men, but not in middle-aged women. The competitive inhibition of l-arginine may contribute to this decrease in men.
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Affiliation(s)
- Akihiro Nakamura
- Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan.
| | - Shoko Kajitani
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kenjiro Sato
- Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan
| | - Masanori Kanazawa
- Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan
| | - Masateru Kondo
- Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan
| | - Hideaki Endo
- Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan
| | - Eiji Nozaki
- Department of Cardiology, Iwate Prefectural Central Hospital, 1-4-1 Ueda, Morioka, 020-0066, Japan
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Yao S, Agyei D, Udenigwe CC. Structural Basis of Bioactivity of Food Peptides in Promoting Metabolic Health. ADVANCES IN FOOD AND NUTRITION RESEARCH 2018; 84:145-181. [PMID: 29555068 DOI: 10.1016/bs.afnr.2017.12.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Bioactive peptides have many structural features that enable them to become functional in controlling several biological processes in the body, especially those related to metabolic health. This chapter provides an overview of the multiple targets of food-derived peptides against metabolic health problems (e.g., hypertension, dyslipidemia, hyperglycemia, oxidative stress) and discusses the importance of structural chemistry in determining the bioactivities of peptides and protein hydrolysates.
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Affiliation(s)
- Shixiang Yao
- Southwest University, Chongqing, PR China; University of Ottawa, Ottawa, ON, Canada
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7
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Mekata T, Kono T, Satoh J, Yoshida M, Mori K, Sato T, Miyazato M, Ida T. Purification and characterization of bioactive peptides RYamide and CCHamide in the kuruma shrimp Marsupenaeus japonicus. Gen Comp Endocrinol 2017; 246:321-330. [PMID: 28062303 DOI: 10.1016/j.ygcen.2017.01.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 12/01/2016] [Accepted: 01/02/2017] [Indexed: 11/24/2022]
Abstract
To understand the regulation systems of appetite, bioactive peptides from the kuruma shrimp Marsupenaeus japonicus (Mj) were isolated and purified by reverse pharmacological assays using CHO cells expressing the Drosophila melanogaster G-protein-coupled receptors (GPCRs) CG5811 (a RYamide receptor) or CG14593 (a CCHamide-2 receptor). Four peptides having binding activity to GPCRs were obtained and named Mj RYamide-1, Mj RYamide-2, Mj RYamide-3, and Mj CCHamide. Genes encoding the prepropeptides of these peptides were identified using kuruma shrimp transcriptome databases. The Mj prepro-RYamide gene encodes a 130-amino acid polypeptide containing Mj RYamide-1, Mj RYamide-2, and Mj RYamide-3, whereas the Mj prepro-CCHamide gene encodes a 119-amino acid polypeptide containing a single Mj CCHamide peptide. The expression of these genes was confirmed in various neuronal organs including the brain and ventral nerve cord. In addition, prepro-RYamide gene expression is significantly reduced in the brain after starvation. RYamides may thus be associated with regulation of feeding or digestion. Changes in kayak (the c-fos ortholog in invertebrates) gene expression after administration of synthetic peptides were also investigated. Mj kayak expression levels are upregulated in hepatopancreas after treatment with Mj RYamide-3 or CCHamide. Thus, the peptides isolated in this study may have some regulatory effect on cellular metabolism in aquacultured invertebrates.
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Affiliation(s)
- Tohru Mekata
- National Research Institute of Aquaculture, Japan Fisheries Research and Education Agency, Mie 516-0193, Japan
| | - Tomoya Kono
- Department of Biochemistry and Applied Biosciences, Faculty of Agriculture, University of Miyazaki, Miyazaki 889-2192, Japan
| | - Jun Satoh
- National Research Institute of Aquaculture, Japan Fisheries Research and Education Agency, Mie 516-0193, Japan
| | - Morikatsu Yoshida
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan
| | - Kenji Mori
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan
| | - Takahiro Sato
- Molecular Genetics, Institute of Life Sciences, Kurume University, Fukuoka 839-0864, Japan
| | - Mikiya Miyazato
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan
| | - Takanori Ida
- Division of Searching and Identification of Bioactive Peptides, Department of Bioactive Peptides, Frontier Science Research Center, University of Miyazaki, Miyazaki 889-1692, Japan; Division of Research & Inspection for Infectious Diseases, Center for Animal Disease Control, University of Miyazaki, Miyazaki 889-1692, Japan.
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8
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Tavares ALP, Cox TC, Maxson RM, Ford HL, Clouthier DE. Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development. Development 2017; 144:2021-2031. [PMID: 28455376 DOI: 10.1242/dev.145144] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 04/18/2017] [Indexed: 12/20/2022]
Abstract
Jaw morphogenesis is a complex event mediated by inductive signals that establish and maintain the distinct developmental domains required for formation of hinged jaws, the defining feature of gnathostomes. The mandibular portion of pharyngeal arch 1 is patterned dorsally by Jagged-Notch signaling and ventrally by endothelin receptor A (EDNRA) signaling. Loss of EDNRA signaling disrupts normal ventral gene expression, the result of which is homeotic transformation of the mandible into a maxilla-like structure. However, loss of Jagged-Notch signaling does not result in significant changes in maxillary development. Here we show in mouse that the transcription factor SIX1 regulates dorsal arch development not only by inducing dorsal Jag1 expression but also by inhibiting endothelin 1 (Edn1) expression in the pharyngeal endoderm of the dorsal arch, thus preventing dorsal EDNRA signaling. In the absence of SIX1, but not JAG1, aberrant EDNRA signaling in the dorsal domain results in partial duplication of the mandible. Together, our results illustrate that SIX1 is the central mediator of dorsal mandibular arch identity, thus ensuring separation of bone development between the upper and lower jaws.
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Affiliation(s)
- Andre L P Tavares
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Timothy C Cox
- Department of Pediatrics (Craniofacial Medicine), University of Washington, and Center for Developmental Biology & Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA 98101, USA
| | - Robert M Maxson
- Department of Biochemistry and Molecular Biology and Norris Cancer Center, University of Southern California, Los Angeles, CA 87654, USA
| | - Heide L Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - David E Clouthier
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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9
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Archer CR, Robinson EL, Drawnel FM, Roderick HL. Endothelin-1 promotes hypertrophic remodelling of cardiac myocytes by activating sustained signalling and transcription downstream of endothelin type A receptors. Cell Signal 2017; 36:240-254. [PMID: 28412414 PMCID: PMC5486433 DOI: 10.1016/j.cellsig.2017.04.010] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 03/21/2017] [Accepted: 04/12/2017] [Indexed: 02/07/2023]
Abstract
G-protein coupled receptor (GPCR) mediated activation of the MAPK signalling cascade is a key pathway in the induction of hypertrophic remodelling of the heart – a response to pathological cues including hypertension and myocardial infarction. While levels of pro-hypertrophic hormone agonists of GPCRs increase during periods of greater workload to enhance cardiac output, hypertrophy does not necessarily result. Here we investigated the relationship between the duration of exposure to the pro-hypertrophic GPCR agonist endothelin-1 (ET-1) and the induction of hypertrophic remodelling in neonatal rat ventricular myocytes (NRVM) and in the adult rat heart in vivo. Notably, a 15 min pulse of ET-1 was sufficient to induce markers of hypertrophy that were present when measured at 24 h in vivo and 48 h in vitro. The persistence of ET-1 action was insensitive to ET type A receptor (ETA receptor) antagonism with BQ123. The extended effects of ET-1 were dependent upon sustained MAPK signalling and involved persistent transcription. Inhibitors of endocytosis however conferred sensitivity upon the hypertrophic response to BQ123, suggesting that endocytosis of ETA receptors following ligand binding preserves their active state by protection against antagonist. Contrastingly, α1 adrenergic-induced hypertrophic responses required the continued presence of agonist and were sensitive to antagonist. These studies shed new light on strategies to pharmacologically intervene in the action of different pro-hypertrophic mediators.
Acute ET-1 exposure elicits a long-lasting cardiac myocyte hypertrophic response. ET-1 effects depend on persistent MAPK signalling and active transcription. ET-1 elicited hypertrophy is insensitive to subsequent ETA receptor antagonism. Endocytosis inhibition potentiates ET-1-induction of hypertrophy markers. Endocytosis inhibition sensitises effects of ET-1 to ETA receptor antagonist.
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Affiliation(s)
| | - Emma L Robinson
- Laboratory of Experimental Cardiology, Dept. of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium
| | - Faye M Drawnel
- The Babraham Institute, Babraham, Cambridge, CB22 3AT, UK
| | - H Llewelyn Roderick
- Laboratory of Experimental Cardiology, Dept. of Cardiovascular Sciences, KU Leuven, Campus Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium.
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10
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Iklé JM, Tavares ALP, King M, Ding H, Colombo S, Firulli BA, Firulli AB, Targoff KL, Yelon D, Clouthier DE. Nkx2.5 regulates endothelin converting enzyme-1 during pharyngeal arch patterning. Genesis 2017; 55. [PMID: 28109039 DOI: 10.1002/dvg.23021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 12/11/2022]
Abstract
In gnathostomes, dorsoventral (D-V) patterning of neural crest cells (NCC) within the pharyngeal arches is crucial for the development of hinged jaws. One of the key signals that mediate this process is Endothelin-1 (EDN1). Loss of EDN1 binding to the Endothelin-A receptor (EDNRA) results in loss of EDNRA signaling and subsequent facial birth defects in humans, mice and zebrafish. A rate-limiting step in this crucial signaling pathway is the conversion of immature EDN1 into a mature active form by Endothelin converting enzyme-1 (ECE1). However, surprisingly little is known about how Ece1 transcription is induced or regulated. We show here that Nkx2.5 is required for proper craniofacial development in zebrafish and acts in part by upregulating ece1 expression. Disruption of nkx2.5 in zebrafish embryos results in defects in both ventral and dorsal pharyngeal arch-derived elements, with changes in ventral arch gene expression consistent with a disruption in Ednra signaling. ece1 mRNA rescues the nkx2.5 morphant phenotype, indicating that Nkx2.5 functions through modulating Ece1 expression or function. These studies illustrate a new function for Nkx2.5 in embryonic development and provide new avenues with which to pursue potential mechanisms underlying human facial disorders.
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Affiliation(s)
- Jennifer M Iklé
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045
| | - Andre L P Tavares
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045
| | - Marisol King
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045
| | - Hailei Ding
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045
| | - Sophie Colombo
- Division of Cardiology, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, 10032
| | - Beth A Firulli
- Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Indianapolis, 46202
| | - Anthony B Firulli
- Departments of Anatomy and Medical, Biochemistry, and Molecular Genetics, Indiana Medical School, Riley Heart Research Center, Herman B Wells Center for Pediatric Research, Division of Pediatric Cardiology, Indianapolis, 46202
| | - Kimara L Targoff
- Division of Cardiology, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, 10032
| | - Deborah Yelon
- Division of Biological Sciences, University of California, San Diego, La Jolla, California, 92093
| | - David E Clouthier
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, 80045
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11
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Square T, Jandzik D, Cattell M, Hansen A, Medeiros DM. Embryonic expression of endothelins and their receptors in lamprey and frog reveals stem vertebrate origins of complex Endothelin signaling. Sci Rep 2016; 6:34282. [PMID: 27677704 PMCID: PMC5039696 DOI: 10.1038/srep34282] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 09/09/2016] [Indexed: 12/19/2022] Open
Abstract
Neural crest cells (NCCs) are highly patterned embryonic cells that migrate along stereotyped routes to give rise to a diverse array of adult tissues and cell types. Modern NCCs are thought to have evolved from migratory neural precursors with limited developmental potential and patterning. How this occurred is poorly understood. Endothelin signaling regulates several aspects of NCC development, including their migration, differentiation, and patterning. In jawed vertebrates, Endothelin signaling involves multiple functionally distinct ligands (Edns) and receptors (Ednrs) expressed in various NCC subpopulations. To test the potential role of endothelin signaling diversification in the evolution of modern, highly patterned NCC, we analyzed the expression of the complete set of endothelin ligands and receptors in the jawless vertebrate, the sea lamprey (Petromyzon marinus). To better understand ancestral features of gnathostome edn and ednr expression, we also analyzed all known Endothelin signaling components in the African clawed frog (Xenopus laevis). We found that the sea lamprey has a gnathsotome-like complement of edn and ednr duplicates, and these genes are expressed in patterns highly reminiscent of their gnathostome counterparts. Our results suggest that the duplication and specialization of vertebrate Endothelin signaling coincided with the appearance of highly patterned and multipotent NCCs in stem vertebrates.
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Affiliation(s)
- Tyler Square
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA
| | - David Jandzik
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA
- Department of Zoology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, 84215, Slovakia
| | - Maria Cattell
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA
| | - Andrew Hansen
- Department of Ecology and Evolutionary Biology, University of Colorado, Boulder, CO 80309, USA
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Zhu LA, Fang NY, Gao PJ, Jin X, Wang HY, Liu Z. Differential ERK1/2 Signaling and Hypertrophic Response to Endothelin-1 in Cardiomyocytes from SHR and Wistar-Kyoto Rats: A Potential Target for Combination Therapy of Hypertension. Curr Vasc Pharmacol 2016; 13:467-74. [PMID: 25360842 PMCID: PMC4997939 DOI: 10.2174/1570161112666141014150007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 04/29/2014] [Accepted: 05/21/2014] [Indexed: 11/26/2022]
Abstract
Extracellular signal regulated kinase½ (ERK1/2) signaling is critical to endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. This study was to investigate ERK1/2 signaling and hypertrophic response to ET-1 stimulation in cardiomyocytes (CMs) from spontaneous hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Primary neonatal SHR and WKY CMs were exposed to ET-1 for up to 24 hrs. Minimal basal ERK1/2 phosphorylation was present in WKY CMs, while a significant baseline ERK1/2 phosphorylation was observed in SHR CMs. ET-1 induced a time- and dose-dependent increase in ERK1/2 phosphorylation in both SHR and WKY CMs. However, ET-1-induced ERK1/2 activation occurred much earlier with significantly higher peak phosphorylation level, and stayed elevated for longer duration in SHR CMs than that in WKY CMs. ET-1-induced hypertrophic response was more prominent in SHR CMs than that in WKY CMs as reflected by increased cell surface area, intracellular actin density, and protein synthesis. Pre-treatment with ERK1/2 phosphorylation inhibitor PD98059 completely prevented ET-1-induced ERK1/2 phosphorylation and increases in cell surface area and protein synthesis in SHR and WKY CMs. The specific PI3 kinase inhibitor LY294002 blocked ET-1-induced Akt and ERK1/2 phosphorylation, and protein synthesis in CMs. These data indicated that ERK1/2 signaling was differentially enhanced in CMs, and was associated with increased cardiac hypertrophic response to ET-1 in SHR. ET-1-induced ERK1/2 activation and cardiac hypertrophy appeared to be mediated via PI3 kinase/Akt signaling in SHR and WKY. The differential ERK1/2 activation in SHR CMs by ET-1 might represent a potential target for combination therapy of hypertension.
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Affiliation(s)
| | - Ning-Yuan Fang
- Department of Geriatrics, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shan-Dong Middle Road, Shanghai 200001, China.
| | | | | | | | - Zhenguo Liu
- Davis Heart & Lung Research Institute, the Ohio State University Medical Center, DHLRI Suite 200; 473 West 12th Ave, Columbus, OH 43210, USA.
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Kobayashi Y, Yoshimoto Y, Yamamoto Y, Kimura K, Okuda K. Roles of EDNs in regulating oviductal NO synthesis and smooth muscle motility in cows. Reproduction 2016; 151:615-22. [PMID: 26980806 DOI: 10.1530/rep-15-0586] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 03/15/2016] [Indexed: 12/12/2022]
Abstract
Endothelins (EDNs) participate in various physiological events including smooth muscle contraction, nitric oxide (NO) synthesis, and embryonic development. In this study, we investigated the regional roles of EDNs produced by bovine oviductal epithelial cells in NO synthesis and smooth muscle motility. Quantification of mRNA expressions indicated that expression of EDN receptor B (EDNRB) in the ampullary region was higher after ovulation than before ovulation, whereas expression of EDNRA in the isthmic region was higher after ovulation than before ovulation. Immunohistochemistry revealed that the EDN receptors (EDNRA and EDNRB) were expressed in the epithelium, whereas smooth muscle showed positive staining only for EDNRA. The expressionsPlease suggest whether 'NOS2' can be treated as the updated symbol for 'iNOS' as per gene nomenclature. of inducible NO synthase (iNOS) protein and its mRNA (NOS2) in cultured epithelial cells isolated from the ampulla were stimulated by EDN1, but not by EDN2 or EDN3, after 1h of incubation. In isthmic epithelial cells, none of the EDNs affected the expression of NOS2 Isometric contraction tests indicated that spontaneous waves were strong in the isthmic region but weak in the ampullary region. EDN1 modulated smooth muscle motility in both the regions. The overall findings suggest that EDN1 plays region-specific roles in smooth muscle motility and epithelial NO synthesis, providing an optimal oviductal microenvironment for transport of gametes, fertilization, and development/transport of early embryo.
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Affiliation(s)
- Yoshihiko Kobayashi
- Laboratory of Reproductive PhysiologyGraduate School of Environmental and Life Science, Okayama University, Okayama, Japan
| | - Yuka Yoshimoto
- Laboratory of Reproductive PhysiologyGraduate School of Environmental and Life Science, Okayama University, Okayama, Japan
| | - Yuki Yamamoto
- Laboratory of Reproductive PhysiologyGraduate School of Environmental and Life Science, Okayama University, Okayama, Japan
| | - Koji Kimura
- Laboratory of Reproductive PhysiologyGraduate School of Environmental and Life Science, Okayama University, Okayama, Japan
| | - Kiyoshi Okuda
- Laboratory of Reproductive PhysiologyGraduate School of Environmental and Life Science, Okayama University, Okayama, Japan Obihiro University of Agriculture and Veterinary MedicineHokkaido, Japan
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Saleh L, Verdonk K, Visser W, van den Meiracker AH, Danser AHJ. The emerging role of endothelin-1 in the pathogenesis of pre-eclampsia. Ther Adv Cardiovasc Dis 2016; 10:282-93. [PMID: 26755746 DOI: 10.1177/1753944715624853] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Pre-eclampsia (PE) is the most frequently encountered medical complication during pregnancy. It is characterized by a rise in systemic vascular resistance with a relatively low cardiac output and hypovolemia, combined with severe proteinuria. Despite the hypovolemia, renin-angiotensin system (RAS) activity is suppressed and aldosterone levels are decreased to the same degree as renin. This suggests that the RAS is not the cause of the hypertension in PE, but rather that its suppression is the consequence of the rise in blood pressure. Abnormal placentation early in pregnancy is widely assumed to be an important initial event in the onset of PE. Eventually, this results in the release of anti-angiogenic factors [in particular, soluble Fms-like tyrosine kinase-1 (sFlt-1)] and cytokines, leading to generalized vascular dysfunction. Elevated sFlt-1 levels bind and inactivate vascular endothelial growth factor (VEGF). Of interest, VEGF inhibition with drugs like sunitinib, applied in cancer patients, results in a PE-like syndrome, characterized by hypertension, proteinuria and renal toxicity. Both in cancer patients treated with sunitinib and in pregnant women with PE, significant rises in endothelin-1 occur. Multiple regression analysis revealed that endothelin-1 is an independent determinant of the hypertension and proteinuria in PE, and additionally a renin suppressor. Moreover, studies in animal models representative of PE, have shown that endothelin receptor blockers prevent the development of this disease. Similarly, endothelin receptor blockers are protective during sunitinib treatment. Taken together, activation of the endothelin system emerges as an important pathway causing the clinical manifestations of PE. This paper critically addresses this concept, taking into consideration both clinical and preclinical data, and simultaneously discusses the therapeutic consequences of this observation.
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Affiliation(s)
- Langeza Saleh
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsDivision Obstetrics & Prenatal Medicine, Department of Obstetrics & Gynaecology, Erasmus MC, Rotterdam, The Netherlands
| | - Koen Verdonk
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - Willy Visser
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The NetherlandsDivision Obstetrics & Prenatal Medicine, Department of Obstetrics & Gynaecology, Erasmus MC, Rotterdam, The Netherlands
| | - Anton H van den Meiracker
- Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
| | - A H Jan Danser
- Department of Internal Medicine, Division of Vascular Medicine & Pharmacology, Room EE1418, Erasmus MC, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands
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Kumarathasan P, Blais E, Saravanamuthu A, Bielecki A, Mukherjee B, Bjarnason S, Guénette J, Goegan P, Vincent R. Nitrative stress, oxidative stress and plasma endothelin levels after inhalation of particulate matter and ozone. Part Fibre Toxicol 2015. [PMID: 26376633 DOI: 10.1186/s12989‐015‐0103‐7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND While exposure to ambient air contaminants is clearly associated with adverse health outcomes, disentangling mechanisms of pollutant interactions remains a challenge. OBJECTIVES We aimed at characterizing free radical pathways and the endothelinergic system in rats after inhalation of urban particulate matter, ozone, and a combination of particles plus ozone to gain insight into pollutant-specific toxicity mechanisms and any effect modification due to air pollutant mixtures. METHODS Fischer 344 rats were exposed for 4 h to a 3 × 3 concentration matrix of ozone (0, 0.4, 0.8 ppm) and EHC-93 particles (0, 5, 50 mg/m(3)). Bronchoalveolar lavage fluid (BALF), BAL cells, blood and plasma were analysed for biomarkers of effects immediately and 24 h post-exposure. RESULTS Inhalation of ozone increased (p < 0.05) lipid oxidation products in BAL cells immediately post-exposure, and increased (p < 0.05) total protein, neutrophils and mature macrophages in the BALF 24 h post-exposure. Ozone increased (p < 0.05) the formation of reactive oxygen species (ROS), assessed by m-, p-, o-tyrosines in BALF (Ozone main effects, p < 0.05), while formation of reactive nitrogen species (RNS), indicated by 3-nitrotyrosine, correlated with dose of urban particles (EHC-93 main effects or EHC-93 × Ozone interactions, p < 0.05). Carboxyhemoglobin levels in blood exhibited particle exposure-related increase (p < 0.05) 24 h post recovery. Plasma 3-nitrotyrosine and o-tyrosine were increased (p < 0.05) after inhalation of particles; the effect on 3-nitrotyrosine was abrogated after exposure to ozone plus particles (EHC-93 × Ozone, p < 0.05). Big endothelin-1 (BET-1) and ET-1 were increased in plasma after inhalation of particles or ozone alone, but the effects appeared to be attenuated by co-exposure to contaminants (EHC-93 × Ozone, p < 0.05). Plasma ET levels were positively correlated (p < 0.05) with BALF m- and o-tyrosine levels. CONCLUSIONS Pollutant-specific changes can be amplified or abrogated following multi-pollutant exposures. Oxidative and nitrative stress in the lung compartment may contribute to secondary extra-pulmonary ROS/RNS formation. Nitrative stress and endothelinergic imbalance emerge as potential key pathways of air pollutant health effects, notably of ambient particulate matter.
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Affiliation(s)
- Prem Kumarathasan
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada.
| | - Erica Blais
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Anushuyadevi Saravanamuthu
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Agnieszka Bielecki
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Ballari Mukherjee
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Stephen Bjarnason
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
| | - Josée Guénette
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
| | - Patrick Goegan
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
| | - Renaud Vincent
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
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16
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Kumarathasan P, Blais E, Saravanamuthu A, Bielecki A, Mukherjee B, Bjarnason S, Guénette J, Goegan P, Vincent R. Nitrative stress, oxidative stress and plasma endothelin levels after inhalation of particulate matter and ozone. Part Fibre Toxicol 2015; 12:28. [PMID: 26376633 PMCID: PMC4573945 DOI: 10.1186/s12989-015-0103-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 09/02/2015] [Indexed: 01/08/2023] Open
Abstract
Background While exposure to ambient air contaminants is clearly associated with adverse health outcomes, disentangling mechanisms of pollutant interactions remains a challenge. Objectives We aimed at characterizing free radical pathways and the endothelinergic system in rats after inhalation of urban particulate matter, ozone, and a combination of particles plus ozone to gain insight into pollutant-specific toxicity mechanisms and any effect modification due to air pollutant mixtures. Methods Fischer 344 rats were exposed for 4 h to a 3 × 3 concentration matrix of ozone (0, 0.4, 0.8 ppm) and EHC-93 particles (0, 5, 50 mg/m3). Bronchoalveolar lavage fluid (BALF), BAL cells, blood and plasma were analysed for biomarkers of effects immediately and 24 h post-exposure. Results Inhalation of ozone increased (p < 0.05) lipid oxidation products in BAL cells immediately post-exposure, and increased (p < 0.05) total protein, neutrophils and mature macrophages in the BALF 24 h post-exposure. Ozone increased (p < 0.05) the formation of reactive oxygen species (ROS), assessed by m-, p-, o-tyrosines in BALF (Ozone main effects, p < 0.05), while formation of reactive nitrogen species (RNS), indicated by 3-nitrotyrosine, correlated with dose of urban particles (EHC-93 main effects or EHC-93 × Ozone interactions, p < 0.05). Carboxyhemoglobin levels in blood exhibited particle exposure-related increase (p < 0.05) 24 h post recovery. Plasma 3-nitrotyrosine and o-tyrosine were increased (p < 0.05) after inhalation of particles; the effect on 3-nitrotyrosine was abrogated after exposure to ozone plus particles (EHC-93 × Ozone, p < 0.05). Big endothelin-1 (BET-1) and ET-1 were increased in plasma after inhalation of particles or ozone alone, but the effects appeared to be attenuated by co-exposure to contaminants (EHC-93 × Ozone, p < 0.05). Plasma ET levels were positively correlated (p < 0.05) with BALF m- and o-tyrosine levels. Conclusions Pollutant-specific changes can be amplified or abrogated following multi-pollutant exposures. Oxidative and nitrative stress in the lung compartment may contribute to secondary extra-pulmonary ROS/RNS formation. Nitrative stress and endothelinergic imbalance emerge as potential key pathways of air pollutant health effects, notably of ambient particulate matter. Electronic supplementary material The online version of this article (doi:10.1186/s12989-015-0103-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Prem Kumarathasan
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada.
| | - Erica Blais
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Anushuyadevi Saravanamuthu
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Agnieszka Bielecki
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Ballari Mukherjee
- Analytical Biochemistry and Proteomics Laboratory, Environmental Health Centre, Room 233A, 0803C Tunney's Pasture, Ottawa, K1A 0 K9, ON, Canada
| | - Stephen Bjarnason
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
| | - Josée Guénette
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
| | - Patrick Goegan
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
| | - Renaud Vincent
- Inhalation Toxicology Laboratory, Environmental Health Science and Research Bureau, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, K1A 0 K9, ON, Canada
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Correlation between Saliva and Plasma Levels of Endothelin Isoforms ET-1, ET-2, and ET-3. INTERNATIONAL JOURNAL OF PEPTIDES 2015; 2015:828759. [PMID: 25972900 PMCID: PMC4417981 DOI: 10.1155/2015/828759] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2015] [Revised: 03/17/2015] [Accepted: 03/18/2015] [Indexed: 12/20/2022]
Abstract
Although saliva endothelins are emerging as valuable noninvasive cardiovascular biomarkers, reports on the relationship between isoforms in saliva and plasma remain scarce. We measured endothelins in concurrent saliva and plasma samples (n = 30 males; age 18–63) by HPLC-fluorescence. Results revealed statistically significant positive correlations among all isoforms between saliva and plasma: big endothelin-1 (BET-1, 0.55 ± 0.27 versus 3.35 ± 1.28 pmol/mL; r = 0.38, p = 0.041), endothelin-1 (ET-1, 0.52 ± 0.21 versus 3.45 ± 1.28 pmol/mL; r = 0.53, p = 0.003), endothelin-2 (ET-2, 0.21 ± 0.07 versus 1.63 ± 0.66 pmol/mL; r = 0.51, p = 0.004), and endothelin-3 (ET-3, 0.39 ± 0.19 versus 2.32 ± 1.44 pmol/mL; r = 0.75, p < 0.001). Correlations of BET-1, ET-1, and ET-3 within each compartment were positive in both plasma (p < 0.05) and saliva (p ≤ 0.1), whereas ET-2 was not significantly correlated with other isoforms in either plasma or saliva. For all isoforms, concentrations varied on average fivefold between individuals (90th/10th percentiles); individuals with high plasma endothelin levels generally had high saliva endothelin levels. Our results reveal that salivary ET isoform profiles portray the plasmatic profiles and support the view of coordinated regulation of ET-1 and ET-3, but distinct regulatory pathways for ET-2.
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18
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Cre recombinase-regulated Endothelin1 transgenic mouse lines: novel tools for analysis of embryonic and adult disorders. Dev Biol 2015; 400:191-201. [PMID: 25725491 DOI: 10.1016/j.ydbio.2015.01.027] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Revised: 12/31/2014] [Accepted: 01/25/2015] [Indexed: 01/06/2023]
Abstract
Endothelin-1 (EDN1) influences both craniofacial and cardiovascular development and a number of adult physiological conditions by binding to one or both of the known endothelin receptors, thus initiating multiple signaling cascades. Animal models containing both conventional and conditional loss of the Edn1 gene have been used to dissect EDN1 function in both embryos and adults. However, while transgenic Edn1 over-expression or targeted genomic insertion of Edn1 has been performed to understand how elevated levels of Edn1 result in or exacerbate disease states, an animal model in which Edn1 over-expression can be achieved in a spatiotemporal-specific manner has not been reported. Here we describe the creation of Edn1 conditional over-expression transgenic mouse lines in which the chicken β-actin promoter and an Edn1 cDNA are separated by a strong stop sequence flanked by loxP sites. In the presence of Cre, the stop cassette is removed, leading to Edn1 expression. Using the Wnt1-Cre strain, in which Cre expression is targeted to the Wnt1-expressing domain of the central nervous system (CNS) from which neural crest cells (NCCs) arise, we show that stable chicken β-actin-Edn1 (CBA-Edn1) transgenic lines with varying EDN1 protein levels develop defects in NCC-derived tissues of the face, though the severity differs between lines. We also show that Edn1 expression can be achieved in other embryonic tissues utilizing other Cre strains, with this expression also resulting in developmental defects. CBA-Edn1 transgenic mice will be useful in investigating diverse aspects of EDN1-mediated-development and disease, including understanding how NCCs achieve and maintain a positional and functional identity and how aberrant EDN1 levels can lead to multiple physiological changes and diseases.
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19
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Paradis AN, Gay MS, Wilson CG, Zhang L. Newborn hypoxia/anoxia inhibits cardiomyocyte proliferation and decreases cardiomyocyte endowment in the developing heart: role of endothelin-1. PLoS One 2015; 10:e0116600. [PMID: 25692855 PMCID: PMC4334650 DOI: 10.1371/journal.pone.0116600] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 12/12/2014] [Indexed: 12/01/2022] Open
Abstract
In the developing heart, cardiomyocytes undergo terminal differentiation during a critical window around birth. Hypoxia is a major stress to preterm infants, yet its effect on the development and maturation of the heart remains unknown. We tested the hypothesis in a rat model that newborn anoxia accelerates cardiomyocyte terminal differentiation and results in reduced cardiomyocyte endowment in the developing heart via an endothelin-1-dependent mechanism. Newborn rats were exposed to anoxia twice daily from postnatal day 1 to 3, and hearts were isolated and studied at postnatal day 4 (P4), 7 (P7), and 14 (P14). Anoxia significantly increased HIF-1α protein expression and pre-proET-1 mRNA abundance in P4 neonatal hearts. Cardiomyocyte proliferation was significantly decreased by anoxia in P4 and P7, resulting in a significant reduction of cardiomyocyte number per heart weight in the P14 neonates. Furthermore, the expression of cyclin D2 was significantly decreased due to anoxia, while p27 expression was increased. Anoxia has no significant effect on cardiomyocyte binucleation or myocyte size. Consistently, prenatal hypoxia significantly decreased cardiomyocyte proliferation but had no effect on binucleation in the fetal heart. Newborn administration of PD156707, an ETA-receptor antagonist, significantly increased cardiomyocyte proliferation at P4 and cell size at P7, resulting in an increase in the heart to body weight ratio in P7 neonates. In addition, PD156707 abrogated the anoxia-mediated effects. The results suggest that hypoxia and anoxia via activation of endothelin-1 at the critical window of heart development inhibits cardiomyocyte proliferation and decreases myocyte endowment in the developing heart, which may negatively impact cardiac function later in life.
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Affiliation(s)
- Alexandra N. Paradis
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
| | - Maresha S. Gay
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
| | - Christopher G. Wilson
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
- Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, California, United States of America
| | - Lubo Zhang
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, United States of America
- * E-mail:
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20
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Bressan M, Yang PB, Louie JD, Navetta AM, Garriock RJ, Mikawa T. Reciprocal myocardial-endocardial interactions pattern the delay in atrioventricular junction conduction. Development 2014; 141:4149-57. [PMID: 25273084 DOI: 10.1242/dev.110007] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Efficient blood flow depends on two developmental processes that occur within the atrioventricular junction (AVJ) of the heart: conduction delay, which entrains sequential chamber contraction; and valve formation, which prevents retrograde fluid movement. Defects in either result in severe congenital heart disease; however, little is known about the interplay between these two crucial developmental processes. Here, we show that AVJ conduction delay is locally assigned by the morphogenetic events that initiate valve formation. Our data demonstrate that physical separation from endocardial-derived factors prevents AVJ myocardium from becoming fast conducting. Mechanistically, this physical separation is induced by myocardial-derived factors that support cardiac jelly deposition at the onset of valve formation. These data offer a novel paradigm for conduction patterning, whereby reciprocal myocardial-endocardial interactions coordinate the processes of valve formation with establishment of conduction delay. This, in turn, synchronizes the electrophysiological and structural events necessary for the optimization of blood flow through the developing heart.
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Affiliation(s)
- Michael Bressan
- Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3120, USA
| | - PoAn Brian Yang
- Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3120, USA
| | - Jonathan D Louie
- Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3120, USA
| | - Alicia M Navetta
- Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3120, USA
| | - Robert J Garriock
- Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3120, USA
| | - Takashi Mikawa
- Cardiovascular Research Institute, University of California San Francisco, 555 Mission Bay Boulevard South, San Francisco, CA 94143-3120, USA
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21
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Paradis A, Zhang L. Role of endothelin in uteroplacental circulation and fetal vascular function. Curr Vasc Pharmacol 2014; 11:594-605. [PMID: 24063378 DOI: 10.2174/1570161111311050004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Revised: 05/10/2012] [Accepted: 07/12/2012] [Indexed: 01/01/2023]
Abstract
Endothelins are 21-amino acid peptides involved in vascular homeostasis. Three types of peptide have been identified, with endothelin-1 (ET-1) being the most potent vasoconstrictor currently known. Two endothelin receptor subtypes are found in various tissues, including the brain, heart, blood vessel, lung, and placenta. The ETA-receptor is associated with vasoconstriction in vascular smooth muscle. Conversely, the ETB-receptor can elicit a vasoconstrictor effect in vascular smooth muscle and a vasodilator effect via its action in endothelial cells. Both receptors play a key role in maintaining circulatory homeostasis and vascular function. Changes in ET-1 expression are found in various disease states, and overexpression of ET-1 is observed in hypertension and preeclampsia in pregnancy. Placental localization of ET-1 implies a key role in regulating the uteroplacental circulation. Additionally, ET-1 is important in the fetal circulation and is involved in the pulmonary circulation and closure of the ductus arteriosus after birth, as well as fetal growth constriction in utero. ET receptor antagonists and nitric oxide donors may provide therapeutic potential in treating conditions associated with overexpression of ET and hypertension.
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Affiliation(s)
- Alexandra Paradis
- Center for Perinatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, USA.
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22
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Tajsic T, Morrell NW. Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension. Compr Physiol 2013; 1:295-317. [PMID: 23737174 DOI: 10.1002/cphy.c100026] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Pulmonary hypertension is a multifactorial disease characterized by sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Central to the pathobiology of this disease is the process of vascular remodelling. This process involves structural and functional changes to the normal architecture of the walls of pulmonary arteries (PAs) that lead to increased muscularization of the muscular PAs, muscularization of the peripheral, previously nonmuscular, arteries of the respiratory acinus, formation of neointima, and formation of plexiform lesions. Underlying or contributing to the development of these lesions is hypertrophy, proliferation, migration, and resistance to apoptosis of medial cells and this article is concerned with the cellular and molecular mechanisms of these processes. In the first part of the article we focus on the concept of smooth muscle cell phenotype and the difficulties surrounding the identification and characterization of the cell/cells involved in the remodelling of the vessel media and we review the general mechanisms of cell hypertrophy, proliferation, migration and apoptosis. Then, in the larger part of the article, we review the factors identified thus far to be involved in PH intiation and/or progression and review and discuss their effects on pulmonary artery smooth muscle cells (PASMCs) the predominant cells in the tunica media of PAs.
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Affiliation(s)
- Tamara Tajsic
- Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
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Clouthier DE, Passos-Bueno MR, Tavares ALP, Lyonnet S, Amiel J, Gordon CT. Understanding the basis of auriculocondylar syndrome: Insights from human, mouse and zebrafish genetic studies. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2013; 163C:306-17. [PMID: 24123988 DOI: 10.1002/ajmg.c.31376] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Among human birth defect syndromes, malformations affecting the face are perhaps the most striking due to cultural and psychological expectations of facial shape. One such syndrome is auriculocondylar syndrome (ACS), in which patients present with defects in ear and mandible development. Affected structures arise from cranial neural crest cells, a population of cells in the embryo that reside in the pharyngeal arches and give rise to most of the bone, cartilage and connective tissue of the face. Recent studies have found that most cases of ACS arise from defects in signaling molecules associated with the endothelin signaling pathway. Disruption of this signaling pathway in both mouse and zebrafish results in loss of identity of neural crest cells of the mandibular portion of the first pharyngeal arch and the subsequent repatterning of these cells, leading to homeosis of lower jaw structures into more maxillary-like structures. These findings illustrate the importance of endothelin signaling in normal human craniofacial development and illustrate how clinical and basic science approaches can coalesce to improve our understanding of the genetic basis of human birth defect syndromes. Further, understanding the genetic basis for ACS that lies outside of known endothelin signaling components may help elucidate unknown aspects critical to the establishment of neural crest cell patterning during facial morphogenesis.
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Endothelin-1 role in human eye: a review. J Ophthalmol 2011; 2010:354645. [PMID: 21461356 PMCID: PMC3065050 DOI: 10.1155/2010/354645] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2010] [Revised: 11/14/2010] [Accepted: 12/13/2010] [Indexed: 12/05/2022] Open
Abstract
Endothelin is a potent vasoactive peptide occurring in three isotypes, ET-1, ET-2, and ET-3. Through its two main receptors, endothelin A and endothelin B, it is responsible for a variety of physiological functions, primarily blood flow control. Recent evidence from both human and animal models shows involvement of endothelin in diabetes, retinal circulation, and optic neuropathies. Increased circulating levels of endothelin-1 (ET-1) have been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type-2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Experimental studies have shown that chronic ET-1 administration to the optic nerve immediately behind the globe causes neuronal damage, activation of astrocytes, the major glial cell in the anterior optic nerve, and upregulation of endothelin B receptors. This paper outlines the ubiquitous role of endothelin and its potential involvement in ophthalmology.
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Clouthier DE, Garcia E, Schilling TF. Regulation of facial morphogenesis by endothelin signaling: insights from mice and fish. Am J Med Genet A 2010; 152A:2962-73. [PMID: 20684004 PMCID: PMC2974943 DOI: 10.1002/ajmg.a.33568] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Craniofacial morphogenesis is accomplished through a complex set of developmental events, most of which are initiated in neural crest cells within the pharyngeal arches. Local patterning cues from the surrounding environment induce gene expression within neural crest cells, leading to formation of a diverse set of skeletal elements. Endothelin-1 (Edn1) is one of the primary signals that establishes the identity of neural crest cells within the mandibular portion of the first pharyngeal arch. Signaling through its cognate receptor, the endothelin-A receptor, is critical for patterning the ventral/distal portion of the arch (lower jaw) and also participates with Hox genes in patterning more posterior arches. Edn1/Ednra signaling is highly conserved between mouse and zebrafish, and genetic analyses in these two species have provided complementary insights into the patterning cues responsible for establishing the craniofacial complex as well as the genetic basis of facial birth defect syndromes.
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Affiliation(s)
- David E Clouthier
- Department of Craniofacial Biology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, USA.
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26
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Nagai H, Kato A, Kimura F, Shimizu H, Yoshidome H, Ohtsuka M, Furukawa K, Nozawa S, Yoshitomi H, Mitsuhashi N, Takeuchi D, Suda K, Yoshioka I, Miyazaki M. Endothelin-1 aggravates hepatic ischemia/reperfusion injury during obstructive cholestasis in bile duct ligated mice. J Surg Res 2010; 162:46-53. [PMID: 20552721 DOI: 10.1016/j.jss.2007.07.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Cholestasis of the liver is known to be an important risk factor for surgical morbidity and mortality after major hepatectomy. However, the mechanism of liver injury in cholestatic liver is not fully understood. The goal of this study was to investigate the process of liver injury due to hepatic ischemia/reperfusion in obstructive cholestasis. MATERIALS AND METHODS Male C57BL/6 mice underwent common bile duct ligation and subsequently developed obstructive cholestasis. The mice were subjected to 90 min of partial hepatic ischemia followed by reperfusion. RESULTS The survival rate of the mice with cholestatic livers after hepatic ischemia/reperfusion was lower than that of the mice with normal livers. Biochemical and histological analyses showed that the cholestatic mice had a much higher degree of hepatocellular injury after reperfusion than the normal mice. Neutrophil accumulation after reperfusion was significantly decreased in the cholestatic livers; however, considerable microcirculatory disturbances were observed in cholestatic livers after reperfusion. Hepatic stellate cell activation and hepatic expression of endothelin-1 were evaluated by immunohistochemical staining in cholestatic livers after reperfusion. These observations were also associated with increased serum levels of endothelin-1. CONCLUSIONS Hepatic stellate cell activation and increased endothelin-1 production play a crucial role in hepatic ischemia/reperfusion injury in cholestatic liver.
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Affiliation(s)
- Hiroyuki Nagai
- Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
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27
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Lominadze D, Dean WL, Tyagi SC, Roberts AM. Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease. Acta Physiol (Oxf) 2010; 198:1-13. [PMID: 19723026 DOI: 10.1111/j.1748-1716.2009.02037.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Fibrinogen (Fg) is a high molecular weight plasma adhesion protein and a biomarker of inflammation. Many cardiovascular and cerebrovascular disorders are accompanied by increased blood content of Fg. Increased levels of Fg result in changes in blood rheological properties such as increases in plasma viscosity, erythrocyte aggregation, platelet thrombogenesis, alterations in vascular reactivity and compromises in endothelial layer integrity. These alterations exacerbate the complications in peripheral blood circulation during cardiovascular diseases such as hypertension, diabetes and stroke. In addition to affecting blood viscosity by altering plasma viscosity and erythrocyte aggregation, growing experimental evidence suggests that Fg alters vascular reactivity and impairs endothelial cell layer integrity by binding to its endothelial cell membrane receptors and activating signalling mechanisms. The purpose of this review is to discuss experimental data, which demonstrate the effects of Fg causing vascular dysfunction and to offer possible mechanisms for these effects, which could exacerbate microcirculatory complications during cardiovascular diseases accompanied by increased Fg content.
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Affiliation(s)
- D Lominadze
- Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
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Wang JY, Cheng KI, Yu FJ, Tsai HL, Huang TJ, Hsieh JS. Analysis of the Correlation of Plasma NO and ET-1 Levels in Rats With Acute Mesenteric Ischemia. J INVEST SURG 2009; 19:155-61. [PMID: 16809225 DOI: 10.1080/08941930600674652] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mesenteric ischemia is a devastating disease process that frequently challenges clinicians. To enhance the early diagnosis of gut ischemia and judgment of its severity, it may be helpful to detect the unusual existence or increase in biomarkers in the body fluid. The aim of the present study was to evaluate the correlation of plasma nitric oxide (NO) and endothelin-1 (ET-1) levels to mesenteric ischemia using an animal model. Acute mesenteric ischemia (AMI) was produced experimentally by occlusion of the mesenteric vessels in the terminal ileum by the tenting of a thread. The determination of plasma NO and ET-1 levels were obtained before operation (T0, baseline value), and at 10 (T10), 20 (T20), 30 (T30), and 60 (T60) min after the creation of AMI. Sham-operated rats served as controls. After 30 min of experiments, the plasma NO and ET-1 levels were significantly higher in the AMI group than in the control group (both p < .01). Both the plasma NO and ET-1 levels in AMI group increased significantly after 30 min of ischemia (both p < .001 vs. respective baseline value), and they were 60% and 84% above the baseline value, respectively. In addition, ischemic intestinal injury was confirmed by the significantly elevated histological scores in the AMI group after 60 min of ischemia (p < .001). Our preliminary results suggest the possibility of important insights regarding NO and ET-1 changes into the mechanism of pathogenesis in AMI in rats. The increases in plasma NO and ET-1 levels may potentially be noninvasive biomarkers for the early detection of this disease.
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Affiliation(s)
- Jaw-Yuan Wang
- Department of Surgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University and Hospital, Kaohsiung, Taiwan
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Impact of endothelin-1 Lys198Asn polymorphism on coronary artery disease and endorgan damage in hypertensives. Coron Artery Dis 2009; 19:429-34. [PMID: 18923236 DOI: 10.1097/mca.0b013e32830936e5] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
OBJECTIVE Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages. METHODS In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients. RESULTS Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004). CONCLUSION Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.
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Ruest LB, Clouthier DE. Elucidating timing and function of endothelin-A receptor signaling during craniofacial development using neural crest cell-specific gene deletion and receptor antagonism. Dev Biol 2009; 328:94-108. [PMID: 19185569 DOI: 10.1016/j.ydbio.2009.01.005] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2008] [Revised: 12/12/2008] [Accepted: 01/06/2009] [Indexed: 12/31/2022]
Abstract
Cranial neural crest cells (NCCs) play an intimate role in craniofacial development. Multiple signaling cascades participate in patterning cranial NCCs, some of which are regulated by endothelin-A receptor (Ednra) signaling. Ednra(-/-) embryos die at birth from severe craniofacial defects resulting from disruption of neural crest cell patterning and differentiation. These defects include homeotic transformation of lower jaw structures into upper jaw-like structures, suggesting that some cephalic NCCs alter their "identity" in the absence of Ednra signaling. To elucidate the temporal necessity for Ednra signaling in vivo, we undertook two strategies. We first used a conditional knockout strategy in which mice containing a conditionally targeted Ednra allele (Ednra(fl)) were bred with mice from the Hand2-Cre and Wnt1-Cre transgenic mouse strains, two strains in which Cre expression occurs at different time periods within cranial NCCs. In our second approach, we used an Ednra-specific antagonist to treat wild type pregnant mice between embryonic days E8.0 and E10.0, a time frame encompassing the early migration and proliferation of cranial NCCs. The combined results suggest that Ednra function is crucial for NCC development between E8.25 and E9.0, a time period encompassing the arrival of NCCs in the arches and/or early post-migratory patterning. After this time period, Ednra signaling is dispensable. Interestingly, middle ear structures are enlarged and malformed in a majority of Ednra(fl/fl);Wnt1-Cre embryos, instead resembling structures found in extinct predecessors of mammals. These observations suggest that the advent of Ednra signaling in cranial NCCs may have been a crucial event in the evolution of the mammalian middle ear ossicles.
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Affiliation(s)
- Louis-Bruno Ruest
- Department of Craniofacial Biology, University of Colorado Denver, Aurora, CO 80045, USA
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31
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Khimji AK, Shao R, Rockey DC. Divergent transforming growth factor-beta signaling in hepatic stellate cells after liver injury: functional effects on ECE-1 regulation. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 173:716-27. [PMID: 18753413 DOI: 10.2353/ajpath.2008.071121] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
In liver wound healing, transforming growth factor-beta (TGF-beta) plays a critical role in stellate cell activation as well as signaling cascades in the fibrogenic response to injury. We postulate that the TGF-beta-dependent downstream signaling pathway may vary according to the mechanism of stellate cell activation; this study was undertaken to ascertain whether the downstream signaling pathways mediated by TGF-beta vary in different liver injury models. We measured Smad3 and MAP kinase activation after isolating stellate cells from rat livers injured by either bile duct ligation (BDL) or repeated carbon tetrachloride (CCl(4)) administration. Phospho-Smad3 was dramatically up-regulated in stellate cells after CCl(4) injury, but not after BDL-induced injury. TGF-beta signaling in stellate cells activated after BDL was mediated prominently through ERK activation, whereas activation induced by CCl(4) injury or culture led to a cross-signaling mechanism involving both Smad3 and p38. The divergent Smad signaling pathways observed appeared to be attributable to the differential regulation of the early growth response gene-1 (Egr-1), an apparent negative transcriptional factor for Smad3 in our system. In addition, inhibition of ERK activation in stellate cells from BDL-injured liver led to a decrease in expression of endothelin-converting enzyme-1, a critical regulator of endothelin-1. We speculate that TGF-beta signaling proceeds through differential signaling pathways depending on the mechanism of liver injury that leads to stellate cell activation.
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Affiliation(s)
- Al-Karim Khimji
- Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA
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Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa. Exp Eye Res 2008; 86:886-94. [PMID: 18420197 DOI: 10.1016/j.exer.2008.03.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2007] [Revised: 01/11/2008] [Accepted: 03/05/2008] [Indexed: 11/21/2022]
Abstract
Endothelin-1 (ET-1), a potent vaso-active peptide, mediates extracellular matrix regulation resulting in an increase in collagen deposition in various cell types and tissues and has been proposed to play a key role in glaucoma pathology. The role of ET-1 in the regulation of extracellular matrix collagens at the level of optic nerve head is not known. In this study we have examined the role of ET-1 in extracellular matrix collagen regulation in primary cultures of human lamina cribrosa cells. Our hypothesis is that ET-1 increases remodeling of the ECM of cells of the lamina cribrosa. Such actions could contribute to the development of optic neuropathy. QPCR analysis revealed that ET-1 mediated an increase in mRNA levels of collagen type I alpha1 and collagen type VI alpha1 chains at all doses of ET-1 with a significant increase at 1nM and 10nM concentration in LC cells. A dose-dependent increase in collagen type I and type VI protein deposition and secretion was also observed by Western blot in response to ET-1 and was significant at 10nM and 100nM concentrations of ET-1. ET-1 increased the [3H] proline uptake in LC cells suggesting that ET-1 contributed to an increase in total collagen synthesis in LC cells. ET-1-mediated increase in collagen type I, type VI and total collagen synthesis was significantly blocked by the ET(A) receptor antagonist, BQ610, as well as with the ET(B) receptor antagonist, BQ788, suggesting the involvement of both receptor subtypes in ET-1 mediated collagen synthesis in LC cells. These results suggest that ET-1 regulates extracellular matrix collagen synthesis in LC cells and may contribute to ECM remodeling at the level of LC of POAG subjects who have elevated plasma and aqueous humor levels of endothelin-1.
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Garcia RJ, Ittah A, Mirabal S, Figueroa J, Lopez L, Glick AB, Kos L. Endothelin 3 Induces Skin Pigmentation in a Keratin-Driven Inducible Mouse Model. J Invest Dermatol 2008; 128:131-42. [PMID: 17611578 DOI: 10.1038/sj.jid.5700948] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Endothelin 3 (Edn3) encodes a ligand important to developing neural crest cells and is allelic to the spontaneous mouse mutation occurring at the lethal spotting (ls) locus. Edn3(ls/ls) mutants exhibit a spotted phenotype due to reduced numbers of neural crest-derived melanocyte precursors in the skin. In this study, we show that when Edn3 is driven by the keratin 5 promoter and thereby placed proximal to melanocyte lineage cells, adult mice manifest pigmented skin harboring dermal melanocytes. Using a tetracycline inducible system, we show that the postnatal expression of Edn3 is required to maintain these dermal melanocytes, and that early expression of the Edn3 transgene is important to the onset of the hyperpigmentation phenotype. Crosses into Edn3(ls/ls) mutants demonstrate that the Edn3 transgene expression does not fully compensate for the endogenous expression pattern. Crosses into tyrosine kinase receptor Kit(Wv) mutants indicate that Edn3 can partially compensate for Kit's role in early development. Crosses into A(y) mutant mice considerably darkened their yellow coat color suggesting a previously unreported role for endothelin signaling in pigment switching. These results demonstrate that exogenous Edn3 affects both precursors and differentiated melanocytes, leading to a phenotype with characteristics similar to the human skin condition dermal melanocytosis.
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Affiliation(s)
- Roman J Garcia
- Department of Biological Sciences, Florida International University, Miami, Florida 33199, USA
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Tan X, Hu SH, Wang XL. Possible role of nitric oxide in the pathogenesis of pulmonary hypertension in broilers: a synopsis. Avian Pathol 2007; 36:261-7. [PMID: 17620170 DOI: 10.1080/03079450701460765] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Nitric oxide (NO) produced by vascular endothelial cells is an important determinant of the basal tone of small arteries and arterioles. Impaired endothelial NO production has been implicated in the pathophysiology of pulmonary hypertension in humans. Available data suggest that reduction of endothelial NO synthesis, with evidence of reduced endothelial NO synthase expression in pulmonary arterioles, is associated with increased pulmonary vasomotor tone and vascular remodelling in hypertensive broilers. Supplemental l-arginine, a precursor of NO, has been shown to induce flow-dependent pulmonary vasodilation, to prevent reduced endothelial NO synthase expression and to inhibit vascular remodelling in broilers with pulmonary hypertension. Nevertheless, its effect on pulmonary hypertension syndrome incidence is limited. It appears that impaired production of NO is a secondary rather than a causative factor in the pathogenesis of pulmonary hypertension in broilers.
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Affiliation(s)
- Xun Tan
- Department of Veterinary Medicine, Zhejiang University, Hangzhou, PR China
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35
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Combination therapy using inhaled iloprost and sildenafil in a patient with idiopathic pulmonary arterial hypertension. COR ET VASA 2007. [DOI: 10.33678/cor.2007.080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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36
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Fahmy Elnoamany M, Abdelraouf Dawood A. Right Ventricular Myocardial Isovolumic Relaxation Time as Novel Method for Evaluation of Pulmonary Hypertension: Correlation with Endothelin-1 Levels. J Am Soc Echocardiogr 2007; 20:462-9. [DOI: 10.1016/j.echo.2006.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2006] [Indexed: 01/29/2023]
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Forman MB, Stone GW, Jackson EK. Role of Adenosine as Adjunctive Therapy in Acute Myocardial Infarction. ACTA ACUST UNITED AC 2006; 24:116-47. [PMID: 16961725 DOI: 10.1111/j.1527-3466.2006.00116.x] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Although early reperfusion and maintained patency is the mainstay therapy for ST elevation myocardial infarction, experimental studies demonstrate that reperfusion per se induces deleterious effects on viable ischemic cells. Thus "myocardial reperfusion injury" may compromise the full potential of reperfusion therapy and may account for unfavorable outcomes in high-risk patients. Although the mechanisms of reperfusion injury are complex and multifactorial, neutrophil-mediated microvascular injury resulting in a progressive decrease in blood flow ("no-reflow" phenomenon) likely plays an important role. Adenosine is an endogenous nucleoside found in large quantities in myocardial and endothelial cells. It activates four well-characterized receptors producing various physiological effects that attenuate many of the proposed mechanisms of reperfusion injury. The cardio-protective effects of adenosine are supported by its role as a mediator of pre- and post-conditioning. In experimental models, administration of adenosine in the peri-reperfusion period results in a marked reduction in infarct size and improvement in ventricular function. The cardioprotective effects in the canine model have a narrow time window with the drug losing its effect following three hours of ischemia. Several small clinical studies have demonstrated that administration of adenosine with reperfusion therapy reduces infarct size and improves ventricular function. In the larger AMISTAD and AMISTAD II trials a 3-h infusion of adenosine as an adjunct to reperfusion resulted in a striking reduction in infarct size (55-65%). Post hoc analysis of AMISTAD II showed that this was associated with significantly improved early and late mortality in patients treated within 3.17 h of symptoms. An intravenous infusion of adenosine for 3 h should be considered as adjunctive therapy in high risk-patients undergoing reperfusion therapy.
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Affiliation(s)
- Mervyn B Forman
- Emory University and North Atlanta Cardiovascular Associates, P.C., Atlanta, GA, USA
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Yamada T, Ohtani S, Sakurai T, Tsuji T, Kunieda T, Yanagisawa M. Reduced expression of the endothelin receptor type B gene in piebald mice caused by insertion of a retroposon-like element in intron 1. J Biol Chem 2006; 281:10799-807. [PMID: 16500897 DOI: 10.1074/jbc.m512618200] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Mice carrying the piebald mutation exhibit white coat spotting due to the regional absence of neural crest-derived melanocytes. We reported previously that the piebald locus encodes the Ednrb gene and that piebald mice express low levels of structurally intact Ednrb mRNA and EDNRB protein (Hosoda, K., Hammer, R. E., Richardson, J. A., Baynash, A. G., Cheung, J. C., Giaid, A., and Yanagisawa, M. (1994) Cell 79, 1267-1276). Here, we report that both the life span of the Ednrb mRNA and the promoter activity of the Ednrb gene are indistinguishable between wild-type and piebald mice. Introns 2-6 of the Ednrb gene in piebald mice were correctly excised with an efficiency indistinguishable from those in wild-type mice in exon trapping experiments. We found that the piebald allele of the Ednrb gene has a 5.5-kb retroposon-like element in intron 1 possessing canonical sequences of a polyadenylation signal and a splice acceptor site. Abnormal hybrid transcripts carrying exon 1 of the Ednrb gene and a portion of the 5.5-kb element are expressed in piebald mice. The insertion of the 5.5-kb element into a heterologous intron in a mammalian expression vector markedly reduced the expression of the reporter gene. Premature termination and aberrant splicing of the Ednrb transcript caused by the retroposon-like element in intron 1 lead to a reduced level of the normal Ednrb transcript, which is responsible for the partial loss-of-function phenotype of piebald mice.
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MESH Headings
- Alleles
- Alternative Splicing
- Animals
- Base Sequence
- Blotting, Northern
- COS Cells
- Cell Line, Tumor
- Chlorocebus aethiops
- DNA, Complementary/metabolism
- Exons
- Gene Expression Regulation
- Genes, Reporter
- Genetic Vectors
- Introns
- Luciferases/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Mutant Strains
- Models, Genetic
- Molecular Sequence Data
- Phenotype
- Plasmids/metabolism
- RNA, Messenger/metabolism
- Rats
- Receptor, Endothelin B/biosynthesis
- Receptor, Endothelin B/genetics
- Retroelements
- Reverse Transcriptase Polymerase Chain Reaction
- Tissue Distribution
- Transfection
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Affiliation(s)
- Takahisa Yamada
- Howard Hughes Medical Institute and the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9050, USA.
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Abstract
OBJECTIVE To review the pharmacology, pharmacodynamics, and clinical trials evaluating inhaled iloprost in pulmonary arterial hypertension (PAH). DATA SOURCES A MEDLINE search (1996–February 2005) was performed using the key words pulmonary hypertension, iloprost, and epoprostenol. Information regarding Food and Drug Administration approval was obtained via the Internet. STUDY SELECTION AND DATA EXTRACTION All clinical trials using inhaled iloprost in PAH published in English were identified. Additionally, references from the identified articles were reviewed. DATA SYNTHESIS A stable analog of prostacyclin, inhaled iloprost is thought to promote benefit in PAH through vasodilation, antiproliferative effects, and inhibition of platelet aggregation. In a placebo-controlled trial of 203 patients, inhaled iloprost significantly improved the combined endpoint of change in New York Heart Association functional class and 10% improvement in 6-minute walk distance (p = 0.007). Small, short-term clinical trials demonstrated hemodynamic benefits for inhaled iloprost alone and in combination with other pulmonary vasodilating agents. The aerosolized delivery route and low incidence of adverse events are positive attributes for inhaled iloprost, while the frequency of administration and lack of comparative data limit its role in PAH. CONCLUSIONS Currently, inhaled iloprost offers potential benefit for patients with contraindications to bosentan, preference for non-parenteral products, ineligibility for parenteral therapy, or as adjunctive therapy with other pulmonary vasodilators. Larger, long-term clinical trials are needed to solidify the role for inhaled iloprost in the management of PAH.
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Affiliation(s)
- Stacey E Baker
- Department of Pharmacy Services, University of Virginia Health System, Charlottesville, VA 22908-0674, USA.
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40
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Chang FY, Chen CY, Lu CL, Luo JC, Lu RH, Lee SD. Response of blood endothelin-1 and nitric oxide activity in duodenal ulcer patients undergoing Helicobacter pylori eradication. World J Gastroenterol 2005; 11:1048-51. [PMID: 15742413 PMCID: PMC4250770 DOI: 10.3748/wjg.v11.i7.1048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of Helicobacter pylori eradication on endothelin-1 (ET-1) and nitric oxide (NO) in duodenal ulcer (DU) patients.
METHODS: Sixty-six H pylori-infected active DU patients were consecutively enrolled to receive one-week triple therapy (rabeprazole, amoxicillin and metronidazole) and then one-month rabeprazole therapy. They were asked back to determine ulcer and H pylori status using endoscopy one month later. Thirty-seven healthy controls (H pylori +/-: 17/20) were enrolled for comparison. Blood samples were collected in each visit to measure plasma ET-1 and nitrate/nitrite levels using an enzyme immunoassay kit.
RESULTS: Sixty DU patients finished trial per protocol. The ulcer healing and H pylori-eradication rates were 86.7% and 83.3%, respectively. Plasma ET-1 level in DU patients was higher than that of H pylori-negative and positive controls (3.59±0.96 vs 0.89±0.54 vs 0.3±0.2 pg/mL, P<0.01), while nitrate/nitrite levels among them were also significantly different (8.55±0.71 vs 5.27±0.68 vs 6.39±0.92 µmol/L, P<0.05). H pylori eradication diminished ET-1 levels (3.64±0.55 vs 2.64±0.55 pg/mL, P<0.01) but elevated nitrate/nitrite level (8.16±0.84 vs 11.41±1.42 µmol/L, P<0.05).
CONCLUSION: Both plasma ET-1 and nitrate/nitrite levels increase in active DU patients. After an effective H pylori eradication, DU healing is associated with diminished blood ET-1 level and elevated nitrate/nitrite level.
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Affiliation(s)
- Full-Young Chang
- Chief, Division of Gastroenterology, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan, China.
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41
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Mandegar M, Fung YCB, Huang W, Remillard CV, Rubin LJ, Yuan JXJ. Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res 2004; 68:75-103. [PMID: 15313118 DOI: 10.1016/j.mvr.2004.06.001] [Citation(s) in RCA: 217] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2004] [Indexed: 11/28/2022]
Abstract
Pulmonary artery vasoconstriction and vascular remodeling greatly contribute to a sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) in patients with pulmonary arterial hypertension (PAH). The development of PAH involves a complex and heterogeneous constellation of multiple genetic, molecular, and humoral abnormalities, which interact in a complicated manner, presenting a final manifestation of vascular remodeling in which fibroblasts, smooth muscle and endothelial cells, and platelets all play a role. Vascular remodeling is characterized largely by medial hypertrophy due to enhanced vascular smooth muscle cell proliferation or attenuated apoptosis and to endothelial cell over-proliferation, which can result in lumen obliteration. In addition to other factors, cytoplasmic Ca2+ in particular seems to play a central role as it is involved in both the generation of force through its effects on the contractile machinery, and the initiation and propagation of cell proliferation via its effects on transcription factors, mitogens, and cell cycle components. This review focuses on the role played by cellular factors, circulating factors, and genetic molecular signaling factors that promote a proliferative, antiapoptotic, and vasoconstrictive physiological milieu leading to vascular remodeling.
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MESH Headings
- Animals
- Apoptosis
- Blood Pressure
- Bone Morphogenetic Protein Receptors, Type II
- Calcium Signaling
- Capillaries/pathology
- Capillaries/physiopathology
- Endothelium, Vascular/pathology
- Feedback
- Humans
- Hypertension, Pulmonary/classification
- Hypertension, Pulmonary/etiology
- Hypertension, Pulmonary/pathology
- Hypertension, Pulmonary/physiopathology
- Hypertrophy
- Membrane Glycoproteins/physiology
- Membrane Transport Proteins/physiology
- Models, Biological
- Muscle, Smooth, Vascular/pathology
- Mutation
- Nerve Tissue Proteins/physiology
- Potassium Channels, Voltage-Gated/metabolism
- Protein Serine-Threonine Kinases/genetics
- Pulmonary Artery/pathology
- Pulmonary Artery/physiopathology
- Pulmonary Circulation
- Pulmonary Veins/pathology
- Pulmonary Veins/physiopathology
- Serotonin/physiology
- Serotonin Plasma Membrane Transport Proteins
- Vascular Resistance
- Vasoconstriction
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Affiliation(s)
- Mehran Mandegar
- Department of Medicine, School of Medicine, University of California, San Diego, La Jolla 92093, USA
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42
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Abstract
Primary pulmonary hypertension (PPH) is a rare but often fatal condition characterized by pulmonary artery remodeling leading to chronic elevation of pulmonary artery pressure in the absence of causes. The pathophysiology of PPH is not completely understood, but a number of recent studies have elucidated many possible gentic, hormonal, and environmental factors. Current treatment options slow the progression of the disease but do not halt it. The study of molecular mechanisms that result from mutations in onmental and hormonal modifiers holds great promise for the development of novel therapies that may halt the progression of the disease.
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Affiliation(s)
- Mehran Mandegar
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, LaJolla, CA 92093-0725, USA
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43
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Chan CC, Wang SS, Lee FY, Chang FY, Lin HC, Hou MC, Huang HC, Lee SD. Effects of endothelin-1 on portal-systemic collaterals of common bile duct-ligated cirrhotic rats. Eur J Clin Invest 2004; 34:290-6. [PMID: 15086361 DOI: 10.1111/j.1365-2362.2004.01336.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIMS Endothelin-1 (ET-1) may induce intrahepatic vasoconstriction and consequently increase portal pressure. Endothelin-1 has been shown to exert a direct vasoconstrictive effect on the collateral vessels in partially portal vein-ligated rats with a high degree of portal-systemic shunting. This study investigated the collateral vascular responses to ET-1, the receptors in mediation and the regulation of ET-1 action by nitric oxide and prostaglandin in cirrhotic rats with a relatively low degree of portal-systemic shunting. METHODS The portal-systemic collaterals of common bile duct-ligated (BDL) cirrhotic rats were tested by in situ perfusion. The concentration-response curves of collaterals to graded concentrations of ET-1 (10(-10)-10(-7) m) with or without BQ-123 (ET(A) receptor antagonist, 2 x 10(-6) m), BQ-788 (ET(B) receptor antagonist, 10(-7) m) or both were recorded. In addition, the collateral responses to ET-1 with preincubation of N(omega)-nitro-L-arginine (NNA, 10(-4) M), indomethacin (INDO, 10(-5) M) or in combination were assessed. RESULTS Endothelin-1 significantly increased the perfusion pressures of portal-systemic collaterals. The ET-1-induced constrictive effects were inhibited by BQ-123 or BQ-123 plus BQ-788 but not by BQ-788 alone. The inhibitory effect was greater in the combination group. Pretreatment of NNA or NNA plus INDO equivalently enhanced the response of ET-1 while pretreatment of INDO alone exerted no effect. CONCLUSION Endothelin-1 has a direct vasoconstrictive effect on the collaterals of BDL cirrhotic rats, mainly mediated by ET(A) receptor. Endogenous nitric oxide may play an important role in modulating the effects of ET-1 in the portal-systemic collaterals of BDL cirrhotic rats.
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Affiliation(s)
- C-C Chan
- Taipei Veterans General Hospital, Taipei, Taiwan
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44
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Shi-Wen X, Chen Y, Denton CP, Eastwood M, Renzoni EA, Bou-Gharios G, Pearson JD, Dashwood M, du Bois RM, Black CM, Leask A, Abraham DJ. Endothelin-1 promotes myofibroblast induction through the ETA receptor via a rac/phosphoinositide 3-kinase/Akt-dependent pathway and is essential for the enhanced contractile phenotype of fibrotic fibroblasts. Mol Biol Cell 2004; 15:2707-19. [PMID: 15047866 PMCID: PMC420095 DOI: 10.1091/mbc.e03-12-0902] [Citation(s) in RCA: 258] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The endothelins are a family of endothelium-derived peptides that possess a variety of functions, including vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and promotes myofibroblast contraction and migration, hence contributing to matrix remodeling during tissue repair. Here, we show that addition of ET-1 to normal lung fibroblasts induces expression of proteins that contribute to a contractile phenotype, including alpha-smooth muscle actin (alpha-SMA), ezrin, moesin, and paxillin. We confirm that ET-1 enhances the ability of lung fibroblasts to contract extracellular matrix, a function essential for tissue repair, through induction of de novo protein synthesis. Blockade of the Akt/phosphoinositide 3-kinase (PI3-kinase) pathway with LY294002 and wortmannin prevents the ability of ET-1 to induce alpha-SMA, ezrin, paxillin, and moesin and to promote matrix contraction. Dominant negative rac and Akt blocked the ability of ET-1 to promote formation of alpha-SMA stress fibers. Using specific ET-1 receptor inhibitors, we show that ET-1 induces collagen matrix contraction through the ETA, but not the ETB, receptor. Relative to normal pulmonary fibroblasts, fibroblasts cultured from scars of patients with the fibrotic disease systemic sclerosis (scleroderma) show enhanced ET-1 expression and binding. Systemic sclerosis lung fibroblasts show increased ability to contract a collagen matrix and elevated expression of the procontractile proteins alpha-SMA, ezrin, paxillin, and moesin, which are greatly reduced by antagonizing endogenous ET-1 signaling. Thus, blocking ET-1 or the PI3-kinase/Akt cascades might be beneficial in reducing scar formation in pulmonary fibrosis.
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Affiliation(s)
- Xu Shi-Wen
- Centre for Rheumatology, Royal Free and University College Medical School, London NW3 2PF, United Kingdom
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Xu SW, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, Bou-Gharios G, Denton CP, du Bois RM, Black CM, Leask A, Abraham DJ. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem 2004; 279:23098-103. [PMID: 15044479 DOI: 10.1074/jbc.m311430200] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
The endothelins are a family of endothelium-derived peptides that possess a variety of biological activities, including potent vasoconstriction. Endothelin-1 (ET-1) is up-regulated during tissue repair and pulmonary fibrosis. Here, we use genome-wide expression array analysis to show that the addition of ET-1 (100 nm, 4 h) to normal lung fibroblasts directly induces expression of matrix and matrix-associated genes, including the profibrotic protein CCN2 (connective tissue growth factor, or CTGF). ET-1 induces the MEK/ERK MAP kinase pathway in fibroblasts. Blockade of the MEK/ERK kinase pathway with U0126 abrogates the ability of ET-1 to induce expression of matrix and matrix-associated mRNAs and the CCN2 protein. The CCN2 promoter possesses an ET-1 response element, which maps to the previously identified basal control element-1 (BCE-1) site. Our results suggest that ET-1 induces a program of matrix synthesis in lung fibroblasts and that ET-1 may play a key role in connective tissue deposition during wound repair and in pulmonary fibrosis.
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Affiliation(s)
- Shi-wen Xu
- Centre for Rheumatology, Department of Medicine, Royal Free and University College London, United Kingdom
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46
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Van Woerkom R, Beharry KDA, Modanlou HD, Parker J, Rajan V, Akmal Y, Aranda JV. Influence of morphine and naloxone on endothelin and its receptors in newborn piglet brain vascular endothelial cells: clinical implications in neonatal care. Pediatr Res 2004; 55:147-51. [PMID: 14605251 DOI: 10.1203/01.pdr.0000100756.32861.60] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The present study examines the hypothesis that morphine exposure alters newborn brain vascular endothelial cell production of endothelin (ET)-1, as well as the mRNA expression of its receptors. Newborn piglet vascular endothelial cells were treated with morphine (100 ng/mL media), naloxone (100 ng/mL media), or drug-free media (control) for 6, 24, 48, and 96 h. Media was analyzed for ET-1 and big ET-1 levels and the cells were assessed for ETA and ETB receptor mRNA expression. Morphine exposure progressively increased ET-1 production from 6 to 96 h with concurrent reductions in big ET-1 levels starting at 24 h to almost undetectable levels by 96 h. Whereas ETA receptor mRNA expression increased 2-fold at 6 h and 4-fold at 96 h, ETB receptor mRNA expression remained unchanged. Naloxone exposure caused significant decreases in ET-1 levels, whereas an opposite effect was noted in big ET-1 levels, which increased from 6 through 96 h. Naloxone caused a progressive decrease in ETA receptor mRNA expression at 6 h through 96 h and a 2-fold increase in ETB receptor mRNA expression at 48 and 96 h. Increased ET-1 and its receptors in response to morphine may suggest altered cerebrovascular perfusion and brain metabolism in the immature piglet brain.
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Affiliation(s)
- Richard Van Woerkom
- Division of Neonatology-Perinatal Medicine, Department of Pediatrics, University of California, Irvine, California 92868, USA
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47
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Chongsrisawat V, Chatchatee P, Samransamruajkit R, Vanapongtipagorn P, Chottivittayatarakorn P, Poovorawan Y. Plasma endothelin-1 levels in patients with biliary atresia: possible role in development of portal hypertension. Pediatr Surg Int 2003; 19:478-81. [PMID: 12748798 DOI: 10.1007/s00383-003-0963-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/08/2002] [Indexed: 01/26/2023]
Abstract
BACKGROUND Biliary atresia (BA) is a severe neonatal liver disease characterized by progressive extrahepatic biliary tract and intrahepatic inflammatory process. Hepatic fibrosis and portal hypertension (PH) still occur despite the disappearance of jaundice following successful hepatic portoenterostomy. Endothelin-1 (ET-1) is a potent vasoconstrictor and has been reported to stimulate hepatic collagen synthesis. The aim of this study was to demonstrate the potential role of ET-1 in the pathogenesis of the progressive inflammation, fibrosis and PH in BA. METHODS Thirty pediatric patients with biliary atresia post-hepatic portoenterostomy and 12 healthy children were examined. The ET-1 level was determined by commercially available enzyme-linked immunosorbent assay kits. RESULTS Endothelin-1 levels were elevated in the patients compared with those of the controls (5.45+/-3.34 vs. 2.74+/-2.17 pg/ml, P = 0.01). Moreover, patients with PH also had greater levels of ET-1 than those without PH (6.73+/-3.27 vs. 3.26+/-2.2 pg/ml, P = 0.004). Patients with abnormal transaminase enzymes had significantly higher ET-1 levels than those with normal enzymes (6.43+/-3.33 vs. 3.17+/-2.1 pg/ml, P = 0.01). In the jaundice-free group, endothelin-1 levels were elevated in the patients with PH compared with those without PH (5.93+/-2.15 vs. 2.88+/-2.1 pg/ml, P = 0.02). CONCLUSIONS Our findings showed elevation of plasma ET-1 levels in patients with BA, especially in those with PH. ET-1 levels were also higher in patients with elevated transminase enzymes as well as in the jaundice-free group with PH. ET-1 might play a role in the pathogenesis of the progressive inflammation, fibrosis and PH in BA.
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Affiliation(s)
- V Chongsrisawat
- Department of Pediatrics, Faculty of Medicine, Viral Hepatitis Research Unit, Chulalongkorn University and Hospital, 10330 Bangkok, Thailand
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Shao R, Shi Z, Gotwals PJ, Koteliansky VE, George J, Rockey DC. Cell and molecular regulation of endothelin-1 production during hepatic wound healing. Mol Biol Cell 2003; 14:2327-41. [PMID: 12808033 PMCID: PMC194882 DOI: 10.1091/mbc.02-06-0093] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
During hepatic wound healing, activation of key effectors of the wounding response known as stellate cells leads to a multitude of pathological processes, including increased production of endothelin-1 (ET-1). This latter process has been linked to enhanced expression of endothelin-converting enzyme-1 (ECE-1, the enzyme that converts precursor ET-1 to the mature peptide) in activated stellate cells. Herein, we demonstrate up-regulation of 56- and 62-kDa ECE-1 3'-untranslated region (UTR) mRNA binding proteins in stellate cells after liver injury and stellate cell activation. Binding of these proteins was localized to a CC-rich region in the proximal ECE-1 3' UTR base pairs (the 56-kDa protein) and to a region between 60 and 193 base pairs in the ECE-1 3' UTR mRNA (62 kDa). A functional role for the 3' UTR mRNA/protein interaction was established in a series of reporter assays. Additionally, transforming growth factor-beta1, a cytokine integral to wound healing, stimulated ET-1 production. This effect was due to ECE-1 mRNA stabilization and increased ECE-1 expression in stellate cells, which in turn was a result of de novo synthesis of the identified 56- and 62-kDa ECE-1 3' UTR mRNA binding proteins. These data indicate that liver injury and the hepatic wound healing response lead to ECE-1 mRNA stabilization in stellate cells via binding of 56- and 62-kDa proteins, which in turn are regulated by transforming growth factor-beta. The possibility that the same or similar regulatory events are present in other forms of wound healing is raised.
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Affiliation(s)
- Rong Shao
- Duke University Liver Center, Durham, North Carolina 27710, USA
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Mizunuma K, Ohdan H, Tashiro H, Fudaba Y, Ito H, Asahara T. Prevention of ischemia-reperfusion-induced hepatic microcirculatory disruption by inhibiting stellate cell contraction using rock inhibitor. Transplantation 2003; 75:579-86. [PMID: 12640293 DOI: 10.1097/01.tp.0000052593.16876.af] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND We demonstrated that hepatic stellate cells (HSCs) isolated from rat livers exposed to warm ischemia are significantly contractile when compared with HSCs from intact rat livers. This suggests that ischemia-reperfusion (IR)-induced impairment of sinusoidal microcirculation results, at least in part, from contraction of HSCs. METHODS Rho-associated coiled-coil forming protein serine/threonine kinase (ROCK) is one of the key regulators of HSCs motility. Therefore we investigated whether Y-27632, a p160ROCK-specific inhibitor, has beneficial effects on warm IR injury in an in vivo rat partial liver IR model and a rat orthotopic liver transplantation model. RESULTS After reperfusion following 90 min of warm ischemia, livers in untreated control rats had persistent congestion and impaired mitochondrial respiration, as demonstrated by increasing deoxy-hemoglobin and reduced cytochrome oxidase contents in the hepatic tissues using in vivo near-infrared spectroscopy. Serum levels of transaminase and endothelin (ET)-1 in these rats were markedly increased 1 hr after reperfusion. In contrast, when Y-27632 (3-30 mg/kg) was administered orally, hepatic tissue contents of deoxy-hemoglobin and cytochrome oxidase rapidly normalized. In such animals, the elevation of serum transaminase levels, but not that of ET-1 levels, was significantly suppressed. This is consistent with in vitro data demonstrating that Y-27632 causes HSCs to undergo relaxation even in the presence of ET-1. Moreover, in a rat orthotopic liver transplantation model, Y-27632 pretreatment dramatically improved the survival of recipients with liver grafts subjected to 45 min of warm ischemia. CONCLUSIONS Y-27632 attenuates IR-induced hepatic microcirculation disruption by inhibiting contraction of HSCs.
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Affiliation(s)
- Kazuyuki Mizunuma
- Second Department of Surgery, Hiroshima University, Faculty of Medicine, Hiroshima, Japan
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50
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Yokomori H, Oda M, Ogi M, Yoshimura K, Nomura M, Fujimaki K, Kamegaya Y, Tsukada N, Ishii H. Endothelin-1 suppresses plasma membrane Ca++-ATPase, concomitant with contraction of hepatic sinusoidal endothelial fenestrae. THE AMERICAN JOURNAL OF PATHOLOGY 2003; 162:557-66. [PMID: 12547713 PMCID: PMC1851144 DOI: 10.1016/s0002-9440(10)63849-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 11/04/2002] [Indexed: 12/18/2022]
Abstract
Intracytoplasmic free calcium ions (Ca++) are maintained at a very low concentration in mammalian tissue by extruding Ca++ from the cytoplasm against a steep extracellular Ca++ concentration gradient, mainly through the activity of plasma membrane Ca++ pump-ATPase. The present study aimed to elucidate how endothelin-1 (ET-1) affects the morphology of sinusoidal endothelial fenestrae and ultrastructural distribution of plasma membrane ATPases and intracytoplasmic free Ca++ in isolated rat hepatic sinusoidal endothelial cells. Sinusoidal endothelial fenestrae were observed by scanning electron microscope. Ando's electron cytochemical method was used for ultrastructural localization of Ca++-Mg++-ATPase activity, electron immunogold postembedding method for Ca++ pump-ATPase immunoactivity, and antimonate method for intracytoplasmic free Ca++. Addition of ET-1 to sinusoidal endothelial cells significantly decreased Ca++-Mg++-ATPase activity and Ca++ pump-ATPase expression and increased intracytoplasmic free Ca++ concentration, concomitant with a decrease in diameter of sinusoidal endothelial fenestrae. Co-treatment with Bosentan abolished the actions of ET-1. These results suggest that ET-1 suppresses Ca++-Mg++-ATPase activity and Ca++ pump-ATPase expression on the plasma membrane of sinusoidal endothelial fenestrae, thereby attenuating the extrusion of intracytoplasmic free Ca++ into the extracellular space, leading to an increased concentration of intracytoplasmic free calcium ions and contraction of sinusoidal endothelial fenestrae.
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Affiliation(s)
- Hiroaki Yokomori
- Department of Internal Medicine and the Laboratory of Pathology, Kitasato Medical Center Hospital, Saitama.
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