Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction
Increased levels of reactive oxygen species (ROS) are a hallmark of cardiovascular disease. ROS impact the function of proteins largely through thiol modification leading to redox signalling. Acute, targeted interference with local ROS levels has been difficult. Therefore, how dynamics in redox sign...
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2025-06-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/14/6/705 |
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| author | Melina Lopez Niklas Herrle Bardia Amirmiran Pedro F. Malacarne Julia Werkhäuser Souradeep Chatterjee Carine Kader Victoria Jurisch Xin Wen Maedeh Gheisari Katrin Schäfer Christian Münch Florian Leuschner Ralf Gilsbach Flávia Rezende Ralf P. Brandes |
| author_facet | Melina Lopez Niklas Herrle Bardia Amirmiran Pedro F. Malacarne Julia Werkhäuser Souradeep Chatterjee Carine Kader Victoria Jurisch Xin Wen Maedeh Gheisari Katrin Schäfer Christian Münch Florian Leuschner Ralf Gilsbach Flávia Rezende Ralf P. Brandes |
| author_sort | Melina Lopez |
| collection | DOAJ |
| description | Increased levels of reactive oxygen species (ROS) are a hallmark of cardiovascular disease. ROS impact the function of proteins largely through thiol modification leading to redox signalling. Acute, targeted interference with local ROS levels has been difficult. Therefore, how dynamics in redox signalling impact cardiovascular health is still a matter of current research. An inducible, endothelial cell-specific knock-in mouse model expressing a yeast D-amino acid oxidase enzyme was generated (Hipp11-Flox-Stop-Flox-yDAO-Cdh5-CreERT2<sup>+/0</sup> referred to as ecDAO). DAO releases H<sub>2</sub>O<sub>2</sub> as a by-product of the conversion of D-amino acids into imino acids. The D-amino acid treatment of DAO-expressing cells therefore increases their intracellular H<sub>2</sub>O<sub>2</sub> production. The induction of yDAO in the ecDAO mice was performed with tamoxifen. Subsequently, the mice received D-Alanine (D-Ala, 0.5 M) through drinking water, and the effects on ROS production and vascular and cardiac function were determined. ecDAO induction increased endothelial ROS production as well as ROS production in the lung, which is rich in endothelial cells. The functional consequences of this were, however limited: After minimally invasive myocardial infarction, there was no difference in the outcome between the control (CTL) and ecDAO mice. With respect to vascular function, three days of D-Ala slightly improved vascular function as demonstrated by an increase in the diameter of the carotid artery in vivo and decreased vessel constriction to phenylephrine. Fifty-two days of D-Ala induced cardiac remodelling, increased peripheral resistance, and overoxidation of peroxiredoxins. In conclusion, acute stimulation of endothelial ROS improves cardiovascular function, whereas prolonged ROS exposure deteriorates it. |
| format | Article |
| id | doaj-art-1e052c8a687e4004a23d01aef311c09c |
| institution | OA Journals |
| issn | 2076-3921 |
| language | English |
| publishDate | 2025-06-01 |
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| series | Antioxidants |
| spelling | doaj-art-1e052c8a687e4004a23d01aef311c09c2025-08-20T02:24:17ZengMDPI AGAntioxidants2076-39212025-06-0114670510.3390/antiox14060705Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular DysfunctionMelina Lopez0Niklas Herrle1Bardia Amirmiran2Pedro F. Malacarne3Julia Werkhäuser4Souradeep Chatterjee5Carine Kader6Victoria Jurisch7Xin Wen8Maedeh Gheisari9Katrin Schäfer10Christian Münch11Florian Leuschner12Ralf Gilsbach13Flávia Rezende14Ralf P. Brandes15Institute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyDepartment of Cardiology, University Medical Center Mainz, 55131 Mainz, GermanyInstitute of Molecular Systems Medicine, Goethe University, 60438 Frankfurt am Main, GermanyDepartment of Cardiology, Angiology and Pulmonology, University Hospital Heidelberg, 69118 Heidelberg, GermanyGerman Centre of Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim, 69120 Heidelberg, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyInstitute for Cardiovascular Physiology, Goethe University, 60590 Frankfurt am Main, GermanyIncreased levels of reactive oxygen species (ROS) are a hallmark of cardiovascular disease. ROS impact the function of proteins largely through thiol modification leading to redox signalling. Acute, targeted interference with local ROS levels has been difficult. Therefore, how dynamics in redox signalling impact cardiovascular health is still a matter of current research. An inducible, endothelial cell-specific knock-in mouse model expressing a yeast D-amino acid oxidase enzyme was generated (Hipp11-Flox-Stop-Flox-yDAO-Cdh5-CreERT2<sup>+/0</sup> referred to as ecDAO). DAO releases H<sub>2</sub>O<sub>2</sub> as a by-product of the conversion of D-amino acids into imino acids. The D-amino acid treatment of DAO-expressing cells therefore increases their intracellular H<sub>2</sub>O<sub>2</sub> production. The induction of yDAO in the ecDAO mice was performed with tamoxifen. Subsequently, the mice received D-Alanine (D-Ala, 0.5 M) through drinking water, and the effects on ROS production and vascular and cardiac function were determined. ecDAO induction increased endothelial ROS production as well as ROS production in the lung, which is rich in endothelial cells. The functional consequences of this were, however limited: After minimally invasive myocardial infarction, there was no difference in the outcome between the control (CTL) and ecDAO mice. With respect to vascular function, three days of D-Ala slightly improved vascular function as demonstrated by an increase in the diameter of the carotid artery in vivo and decreased vessel constriction to phenylephrine. Fifty-two days of D-Ala induced cardiac remodelling, increased peripheral resistance, and overoxidation of peroxiredoxins. In conclusion, acute stimulation of endothelial ROS improves cardiovascular function, whereas prolonged ROS exposure deteriorates it.https://www.mdpi.com/2076-3921/14/6/705D-amino acid oxidasechemogeneticoxidative stressreactive oxygen speciesendothelial cellsmyocardial infarction |
| spellingShingle | Melina Lopez Niklas Herrle Bardia Amirmiran Pedro F. Malacarne Julia Werkhäuser Souradeep Chatterjee Carine Kader Victoria Jurisch Xin Wen Maedeh Gheisari Katrin Schäfer Christian Münch Florian Leuschner Ralf Gilsbach Flávia Rezende Ralf P. Brandes Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction Antioxidants D-amino acid oxidase chemogenetic oxidative stress reactive oxygen species endothelial cells myocardial infarction |
| title | Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction |
| title_full | Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction |
| title_fullStr | Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction |
| title_full_unstemmed | Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction |
| title_short | Prolonged In Vivo Chemogenetic Generation of Hydrogen Peroxide by Endothelial Cells Induces Cardiac Remodelling and Vascular Dysfunction |
| title_sort | prolonged in vivo chemogenetic generation of hydrogen peroxide by endothelial cells induces cardiac remodelling and vascular dysfunction |
| topic | D-amino acid oxidase chemogenetic oxidative stress reactive oxygen species endothelial cells myocardial infarction |
| url | https://www.mdpi.com/2076-3921/14/6/705 |
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