Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover

Abstract Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy—specific...

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Autores principales:	Juliana de F. Germano, Chengqun Huang, Jon Sin, Yang Song, Kyle C. Tucker, David J. R. Taylor, Hannaneh Saadaeijahromi, Aleksandr Stotland, Honit Piplani, Roberta A. Gottlieb, Robert M. Mentzer, Allen M. Andres
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bdb64149fffc46618c22d0b61e814c7a
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spelling	oai:doaj.org-article:bdb64149fffc46618c22d0b61e814c7a2021-12-02T14:58:45ZIntermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover10.1038/s41598-020-64924-22045-2322https://doaj.org/article/bdb64149fffc46618c22d0b61e814c7a2020-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-64924-2https://doaj.org/toc/2045-2322Abstract Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy—specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) – in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.Juliana de F. GermanoChengqun HuangJon SinYang SongKyle C. TuckerDavid J. R. TaylorHannaneh SaadaeijahromiAleksandr StotlandHonit PiplaniRoberta A. GottliebRobert M. MentzerAllen M. AndresNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-13 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Juliana de F. Germano Chengqun Huang Jon Sin Yang Song Kyle C. Tucker David J. R. Taylor Hannaneh Saadaeijahromi Aleksandr Stotland Honit Piplani Roberta A. Gottlieb Robert M. Mentzer Allen M. Andres Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover
description	Abstract Given that adverse remodeling is the leading cause of heart failure and death in the USA, there is an urgent unmet need to develop new methods in dealing with this devastating disease. Here we evaluated the efficacy of a short-course glucagon-like peptide-1 receptor agonist therapy—specifically 2-quinoxalinamine, 6,7-dichloro-N-(1,1-dimethylethyl)-3-(methylsulfonyl)-,6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB; aka Compound 2) – in attenuating adverse LV remodeling. We also examined the role, if any, of mitochondrial turnover in this process. Wild-type, Parkin knockout and MitoTimer-expressing mice were subjected to permanent coronary artery ligation, then treated briefly with DMB. LV remodeling and cardiac function were assessed by histology and echocardiography. Autophagy and mitophagy markers were examined by western blot and mitochondrial biogenesis was inferred from MitoTimer protein fluorescence and qPCR. We found that DMB given post-infarction significantly reduced adverse LV remodeling and the decline of cardiac function. This paralleled an increase in autophagy, mitophagy and mitochondrial biogenesis. The salutary effects of the drug were lost in Parkin knockout mice, implicating Parkin-mediated mitophagy as part of its mechanism of action. Our findings suggest that enhancing Parkin-associated mitophagy and mitochondrial biogenesis after infarction is a viable target for therapeutic mitigation of adverse remodeling.
format	article
author	Juliana de F. Germano Chengqun Huang Jon Sin Yang Song Kyle C. Tucker David J. R. Taylor Hannaneh Saadaeijahromi Aleksandr Stotland Honit Piplani Roberta A. Gottlieb Robert M. Mentzer Allen M. Andres
author_facet	Juliana de F. Germano Chengqun Huang Jon Sin Yang Song Kyle C. Tucker David J. R. Taylor Hannaneh Saadaeijahromi Aleksandr Stotland Honit Piplani Roberta A. Gottlieb Robert M. Mentzer Allen M. Andres
author_sort	Juliana de F. Germano
title	Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover
title_short	Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover
title_full	Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover
title_fullStr	Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover
title_full_unstemmed	Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover
title_sort	intermittent use of a short-course glucagon-like peptide-1 receptor agonist therapy limits adverse cardiac remodeling via parkin-dependent mitochondrial turnover
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/bdb64149fffc46618c22d0b61e814c7a
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Intermittent Use of a Short-Course Glucagon-like Peptide-1 Receptor Agonist Therapy Limits Adverse Cardiac Remodeling via Parkin-dependent Mitochondrial Turnover

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