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Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster

The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by...

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Autores principales: Ederer, Karis A., Jin, Kelly, Bouslog, Sarah, Wang, Lu, Gorman, Gregory S., Rowe, Glenn C., Abadir, Peter, Raftery, Daniel, Moellering, Douglas, Promislow, Daniel, Jumbo-Lucioni, Patricia, De Luca, Maria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274988/
https://www.ncbi.nlm.nih.gov/pubmed/30373167
http://dx.doi.org/10.3390/ijms19113351
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author Ederer, Karis A.
Jin, Kelly
Bouslog, Sarah
Wang, Lu
Gorman, Gregory S.
Rowe, Glenn C.
Abadir, Peter
Raftery, Daniel
Moellering, Douglas
Promislow, Daniel
Jumbo-Lucioni, Patricia
De Luca, Maria
author_facet Ederer, Karis A.
Jin, Kelly
Bouslog, Sarah
Wang, Lu
Gorman, Gregory S.
Rowe, Glenn C.
Abadir, Peter
Raftery, Daniel
Moellering, Douglas
Promislow, Daniel
Jumbo-Lucioni, Patricia
De Luca, Maria
author_sort Ederer, Karis A.
collection PubMed
description The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug’s impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism.
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spelling pubmed-62749882018-12-15 Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster Ederer, Karis A. Jin, Kelly Bouslog, Sarah Wang, Lu Gorman, Gregory S. Rowe, Glenn C. Abadir, Peter Raftery, Daniel Moellering, Douglas Promislow, Daniel Jumbo-Lucioni, Patricia De Luca, Maria Int J Mol Sci Article The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies. Using untargeted metabolomics analysis, we also showed that Lisinopril perturbs the thoracic metabolic network structure by affecting metabolic pathways involved in glycogen degradation, glycolysis, and mevalonate metabolism. The Lisinopril-induced effects on mitochondrial and metabolic parameters, however, are genotype-specific and likely reflect the drug’s impact on nutrient-dependent fitness traits. Accordingly, we found that Lisinopril negatively affects survival under nutrient starvation, an effect that can be blunted by genotype and age in a manner that partially mirrors the drug-induced changes in mitochondrial respiration. In conclusion, our results provide novel and important insights into the role of ACEi in cellular metabolism. MDPI 2018-10-26 /pmc/articles/PMC6274988/ /pubmed/30373167 http://dx.doi.org/10.3390/ijms19113351 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ederer, Karis A.
Jin, Kelly
Bouslog, Sarah
Wang, Lu
Gorman, Gregory S.
Rowe, Glenn C.
Abadir, Peter
Raftery, Daniel
Moellering, Douglas
Promislow, Daniel
Jumbo-Lucioni, Patricia
De Luca, Maria
Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster
title Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster
title_full Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster
title_fullStr Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster
title_full_unstemmed Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster
title_short Age- and Genotype-Specific Effects of the Angiotensin-Converting Enzyme Inhibitor Lisinopril on Mitochondrial and Metabolic Parameters in Drosophila melanogaster
title_sort age- and genotype-specific effects of the angiotensin-converting enzyme inhibitor lisinopril on mitochondrial and metabolic parameters in drosophila melanogaster
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274988/
https://www.ncbi.nlm.nih.gov/pubmed/30373167
http://dx.doi.org/10.3390/ijms19113351
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