Signalling pathways involved in urotensin II induced ventricular myocyte hypertrophy

Sustained pathologic myocardial hypertrophy can result in heart failure(HF); a significant health issue affecting a large section of the population worldwide. In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypert...

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Published in:PloS one 2025-01, Vol.20 (1), p.e0313119
Main Authors: Al Ali, Hadeel S, Rodrigo, Glenn C, Lambert, David G
Format: Article
Language:English
Subjects:
Animals
Antibodies
Biology and Life Sciences
Ca2+/calmodulin-dependent protein kinase II
Calcium (reticular)
Calcium ions
Calcium signalling
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Cardiac muscle
Cardiomegaly - chemically induced
Cardiomegaly - metabolism
Cardiomegaly - pathology
Cardiovascular diseases
Congestive heart failure
Development and progression
Extracellular signal-regulated kinase
Heart diseases
Heart enlargement
Heart failure
Heart Ventricles - metabolism
Heart Ventricles - pathology
Hypertrophy
Kinases
Leak channels
Male
MAP kinase
Medicine and Health Sciences
Membranes
Muscle contraction
Myocytes
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
p38 Mitogen-Activated Protein Kinases - metabolism
Peptides
Proteins
Rats
Rats, Sprague-Dawley
Receptor mechanisms
Receptors
Receptors, G-Protein-Coupled - metabolism
Risk factors
Sarcoplasmic reticulum
Signal transduction
Signal Transduction - drug effects
Urotensins - metabolism
Urotensins - pharmacology
Ventricle
Western blotting
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Rodrigo, Glenn C
Lambert, David G
description Sustained pathologic myocardial hypertrophy can result in heart failure(HF); a significant health issue affecting a large section of the population worldwide. In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypertrophy or whether the high levels contribute to the development of hypertrophy. The aim of this study is to investigate a role of UII and its receptor UT in the development of cardiac hypertrophy and the signalling molecules involved. Ventricular myocytes isolated from adult rat hearts were treated with 200nM UII for 48hours and hypertrophy was quantified from measurements of length/width (L/W) ratio. UII resulted in a change in L/W ratio from 4.53±0.10 to 3.99±0.06; (p
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In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypertrophy or whether the high levels contribute to the development of hypertrophy. The aim of this study is to investigate a role of UII and its receptor UT in the development of cardiac hypertrophy and the signalling molecules involved. Ventricular myocytes isolated from adult rat hearts were treated with 200nM UII for 48hours and hypertrophy was quantified from measurements of length/width (L/W) ratio. UII resulted in a change in L/W ratio from 4.53±0.10 to 3.99±0.06; (p&lt;0.0001) after 48hours. The response is reversed by the UT-antagonist SB657510 (1μM). UT receptor activation by UII resulted in the activation of ERK1/2, p38 and CaMKII signalling pathways measured by Western blotting; these are involved in the induction of hypertrophy. JNK was not involved. Moreover, ERK1/2, P38 and CaMKII inhibitors completely blocked UII-induced hypertrophy. Sarcoplasmic reticulum (SR) Ca2+-leak was investigated in isolated myocytes. There was no significant increase in SR Ca2+-leak. Our results suggest that activation of MAPK and CaMKII signalling pathways are involved in the hypertrophic response to UII. Collectively our data suggest that increased circulating UII may contribute to the development of left ventricular hypertrophy and pharmacological inhibition of the UII/UT receptor system may prove beneficial in reducing adverse remodeling and alleviating contractile dysfunction in heart disease.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0313119</identifier><identifier>PMID: 39820183</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antibodies ; Biology and Life Sciences ; Ca2+/calmodulin-dependent protein kinase II ; Calcium (reticular) ; Calcium ions ; Calcium signalling ; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism ; Cardiac muscle ; Cardiomegaly - chemically induced ; Cardiomegaly - metabolism ; Cardiomegaly - pathology ; Cardiovascular diseases ; Congestive heart failure ; Development and progression ; Extracellular signal-regulated kinase ; Heart diseases ; Heart enlargement ; Heart failure ; Heart Ventricles - metabolism ; Heart Ventricles - pathology ; Hypertrophy ; Kinases ; Leak channels ; Male ; MAP kinase ; Medicine and Health Sciences ; Membranes ; Muscle contraction ; Myocytes ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; p38 Mitogen-Activated Protein Kinases - metabolism ; Peptides ; Proteins ; Rats ; Rats, Sprague-Dawley ; Receptor mechanisms ; Receptors ; Receptors, G-Protein-Coupled - metabolism ; Risk factors ; Sarcoplasmic reticulum ; Signal transduction ; Signal Transduction - drug effects ; Urotensins - metabolism ; Urotensins - pharmacology ; Ventricle ; Western blotting</subject><ispartof>PloS one, 2025-01, Vol.20 (1), p.e0313119</ispartof><rights>Copyright: © 2025 Al Ali et al. 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In HF there is a marked elevation in circulating levels of the peptide urotensin II(UII) but it is unclear whether this is a result of hypertrophy or whether the high levels contribute to the development of hypertrophy. The aim of this study is to investigate a role of UII and its receptor UT in the development of cardiac hypertrophy and the signalling molecules involved. Ventricular myocytes isolated from adult rat hearts were treated with 200nM UII for 48hours and hypertrophy was quantified from measurements of length/width (L/W) ratio. UII resulted in a change in L/W ratio from 4.53±0.10 to 3.99±0.06; (p&lt;0.0001) after 48hours. The response is reversed by the UT-antagonist SB657510 (1μM). UT receptor activation by UII resulted in the activation of ERK1/2, p38 and CaMKII signalling pathways measured by Western blotting; these are involved in the induction of hypertrophy. JNK was not involved. Moreover, ERK1/2, P38 and CaMKII inhibitors completely blocked UII-induced hypertrophy. Sarcoplasmic reticulum (SR) Ca2+-leak was investigated in isolated myocytes. There was no significant increase in SR Ca2+-leak. Our results suggest that activation of MAPK and CaMKII signalling pathways are involved in the hypertrophic response to UII. Collectively our data suggest that increased circulating UII may contribute to the development of left ventricular hypertrophy and pharmacological inhibition of the UII/UT receptor system may prove beneficial in reducing adverse remodeling and alleviating contractile dysfunction in heart disease.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>39820183</pmid><doi>10.1371/journal.pone.0313119</doi><tpages>e0313119</tpages><orcidid>https://orcid.org/0000-0003-4769-8090</orcidid><oa>free_for_read</oa></addata></record>
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subjects Animals
Antibodies
Biology and Life Sciences
Ca2+/calmodulin-dependent protein kinase II
Calcium (reticular)
Calcium ions
Calcium signalling
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Cardiac muscle
Cardiomegaly - chemically induced
Cardiomegaly - metabolism
Cardiomegaly - pathology
Cardiovascular diseases
Congestive heart failure
Development and progression
Extracellular signal-regulated kinase
Heart diseases
Heart enlargement
Heart failure
Heart Ventricles - metabolism
Heart Ventricles - pathology
Hypertrophy
Kinases
Leak channels
Male
MAP kinase
Medicine and Health Sciences
Membranes
Muscle contraction
Myocytes
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - metabolism
Myocytes, Cardiac - pathology
p38 Mitogen-Activated Protein Kinases - metabolism
Peptides
Proteins
Rats
Rats, Sprague-Dawley
Receptor mechanisms
Receptors
Receptors, G-Protein-Coupled - metabolism
Risk factors
Sarcoplasmic reticulum
Signal transduction
Signal Transduction - drug effects
Urotensins - metabolism
Urotensins - pharmacology
Ventricle
Western blotting
title Signalling pathways involved in urotensin II induced ventricular myocyte hypertrophy
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