Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction
Carola Castiello,1,2 Panagiotis Efentakis,1 Panagiota-Efstathia Nikolaou,1 Lydia Symeonidi,1 Christina Chania,1 Ioanna Barla,3 Ifigeneia Akrani,4 Nikolaos Kostomitsopoulos,5 Evangelos Gikas,3 Nikolaos S Thomaidis,3 Emmanuel Mikros,4 Petra Kleinbongard,6 Rossella Fioravanti,2 Clemens Zwergel,2 Sergio...
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Dove Medical Press
2025-06-01
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| author | Castiello C Efentakis P Nikolaou PE Symeonidi L Chania C Barla I Akrani I Kostomitsopoulos N Gikas E Thomaidis NS Mikros E Kleinbongard P Fioravanti R Zwergel C Valente S Mai A Andreadou I |
| author_facet | Castiello C Efentakis P Nikolaou PE Symeonidi L Chania C Barla I Akrani I Kostomitsopoulos N Gikas E Thomaidis NS Mikros E Kleinbongard P Fioravanti R Zwergel C Valente S Mai A Andreadou I |
| author_sort | Castiello C |
| collection | DOAJ |
| description | Carola Castiello,1,2 Panagiotis Efentakis,1 Panagiota-Efstathia Nikolaou,1 Lydia Symeonidi,1 Christina Chania,1 Ioanna Barla,3 Ifigeneia Akrani,4 Nikolaos Kostomitsopoulos,5 Evangelos Gikas,3 Nikolaos S Thomaidis,3 Emmanuel Mikros,4 Petra Kleinbongard,6 Rossella Fioravanti,2 Clemens Zwergel,2 Sergio Valente,2 Antonello Mai,2 Ioanna Andreadou1, † 1Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, 15771, Greece; 2Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, 00185, Italy; 3School of Chemistry, National and Kapodistrian University of Athens, Athens, 15772, Greece; 4Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, 15771, Greece; 5Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece; 6Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, 45122, Germany†Professor Ioanna Andreadou passed away on January 13, 2025Correspondence: Antonello Mai, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy, Tel +390649913392, Fax +3906491491, Email antonello.mai@uniroma1.it Panagiota-Efstathia Nikolaou, Laboratory of Pharmacology, Department of Pharmacy, Panepistimiopolis, Zografou, Athens, 15771, Greece, Tel +30-210-7274146, Fax +30 210 7274827, Email nayanik@pharm.uoa.grPurpose: Sirtuins (SIRTs) play a critical role in redox and metabolic regulation of the myocardium; however, the cardioprotective potential of SIRT5 in terms of infarct size (IS) reduction is still elusive. Herein, we employed the newly synthesized SIRT5-specific agonist, MC3215, developed by our group, to explore for the first time the pharmacological activation of SIRT5 as a target for cardioprotection.Methods and Results: In in vitro screening experiments, SIRT1 and SIRT5 agonists, namely, MC2606 and MC3215, at 1– 20 μ&Mgr; were added to cardiomyoblasts (H9c2) and human endothelial cells (EA.hy-926) during 24 h hypoxia/2 h reoxygenation (H/R). SIRT1 and SIRT5 agonists mitigated H/R injury. Male C57BL/6J mice underwent 30 min ischemia (I) followed by 2 h or 24 h reperfusion (R). Mice received vehicle, the SIRT1 or SIRT5 agonists at 20 and 30 mg/kg at the 20th min of ischemia, and IS was quantified via triphenyl-tetrazolium chloride staining (n=5– 7/group). MC3215-mediated SIRT5 activation reduced IS at 24 h R at 20mg/kg compared to controls (25.18± 2.7% vs 38.80± 4.7%). MC3215 treatment resulted in reduced protein malonylation in all experimental settings. Targeted mass-spectrometry-based metabolomics in the ischemic heart at the 10th min of R suggested increased fatty acid oxidation, as indicated by increased N3-Trimethyllysine and D-pantothenate. Concomitantly, molecular analysis indicated that the SIRT5 agonist activated AMPKα and Reperfusion Injury Salvage Kinase (RISK) pathway. Additionally, at 3 h reperfusion, MC3215 led to increased mitofusin 2 without altering apoptosis, paving towards improved mitochondrial dynamics. Co-administration of SIRT5 inhibitor, TW-37, abrogated MC3215-mediated cardioprotection.Conclusion: SIRT5 pharmacological agonism emerges as a novel cardioprotective target, leading to RISK pathway activation and mitochondria-related metabolic effects, converging at salvaging ischemic myocardium from I/R injury. Keywords: sirtuins, SIRT5, myocardial ischemia/reperfusion injury, cardioprotection |
| format | Article |
| id | doaj-art-e2a492bcbf0348a0bba5376bfa2b17a9 |
| institution | DOAJ |
| issn | 1177-8881 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj-art-e2a492bcbf0348a0bba5376bfa2b17a92025-08-20T03:15:54ZengDove Medical PressDrug Design, Development and Therapy1177-88812025-06-01Volume 19Issue 154895505104290Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial InfarctionCastiello C0Efentakis PNikolaou PESymeonidi L1Chania CBarla I2Akrani I3Kostomitsopoulos N4Gikas E5Thomaidis NS6Mikros EKleinbongard PFioravanti RZwergel C7Valente S8Mai AAndreadou I9Drug Chemistry and TechnologyPharmacyDepartment of ChemistryPharmacyLaboratory Animal FacilityChemistryChemistryOf Drug Chemistry and TechnnologiesDrug Chemistry and TechnologyLaboratory of PharmacologyCarola Castiello,1,2 Panagiotis Efentakis,1 Panagiota-Efstathia Nikolaou,1 Lydia Symeonidi,1 Christina Chania,1 Ioanna Barla,3 Ifigeneia Akrani,4 Nikolaos Kostomitsopoulos,5 Evangelos Gikas,3 Nikolaos S Thomaidis,3 Emmanuel Mikros,4 Petra Kleinbongard,6 Rossella Fioravanti,2 Clemens Zwergel,2 Sergio Valente,2 Antonello Mai,2 Ioanna Andreadou1, † 1Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, 15771, Greece; 2Department of Drug Chemistry and Technologies, Sapienza University of Rome, Rome, 00185, Italy; 3School of Chemistry, National and Kapodistrian University of Athens, Athens, 15772, Greece; 4Department of Pharmaceutical Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, 15771, Greece; 5Biomedical Research Foundation of the Academy of Athens, Athens, 11527, Greece; 6Institute for Pathophysiology, West German Heart and Vascular Center, University of Essen Medical School, Essen, 45122, Germany†Professor Ioanna Andreadou passed away on January 13, 2025Correspondence: Antonello Mai, Department of Drug Chemistry and Technologies, Sapienza University of Rome, Piazzale Aldo Moro 5, Rome, 00185, Italy, Tel +390649913392, Fax +3906491491, Email antonello.mai@uniroma1.it Panagiota-Efstathia Nikolaou, Laboratory of Pharmacology, Department of Pharmacy, Panepistimiopolis, Zografou, Athens, 15771, Greece, Tel +30-210-7274146, Fax +30 210 7274827, Email nayanik@pharm.uoa.grPurpose: Sirtuins (SIRTs) play a critical role in redox and metabolic regulation of the myocardium; however, the cardioprotective potential of SIRT5 in terms of infarct size (IS) reduction is still elusive. Herein, we employed the newly synthesized SIRT5-specific agonist, MC3215, developed by our group, to explore for the first time the pharmacological activation of SIRT5 as a target for cardioprotection.Methods and Results: In in vitro screening experiments, SIRT1 and SIRT5 agonists, namely, MC2606 and MC3215, at 1– 20 μ&Mgr; were added to cardiomyoblasts (H9c2) and human endothelial cells (EA.hy-926) during 24 h hypoxia/2 h reoxygenation (H/R). SIRT1 and SIRT5 agonists mitigated H/R injury. Male C57BL/6J mice underwent 30 min ischemia (I) followed by 2 h or 24 h reperfusion (R). Mice received vehicle, the SIRT1 or SIRT5 agonists at 20 and 30 mg/kg at the 20th min of ischemia, and IS was quantified via triphenyl-tetrazolium chloride staining (n=5– 7/group). MC3215-mediated SIRT5 activation reduced IS at 24 h R at 20mg/kg compared to controls (25.18± 2.7% vs 38.80± 4.7%). MC3215 treatment resulted in reduced protein malonylation in all experimental settings. Targeted mass-spectrometry-based metabolomics in the ischemic heart at the 10th min of R suggested increased fatty acid oxidation, as indicated by increased N3-Trimethyllysine and D-pantothenate. Concomitantly, molecular analysis indicated that the SIRT5 agonist activated AMPKα and Reperfusion Injury Salvage Kinase (RISK) pathway. Additionally, at 3 h reperfusion, MC3215 led to increased mitofusin 2 without altering apoptosis, paving towards improved mitochondrial dynamics. Co-administration of SIRT5 inhibitor, TW-37, abrogated MC3215-mediated cardioprotection.Conclusion: SIRT5 pharmacological agonism emerges as a novel cardioprotective target, leading to RISK pathway activation and mitochondria-related metabolic effects, converging at salvaging ischemic myocardium from I/R injury. Keywords: sirtuins, SIRT5, myocardial ischemia/reperfusion injury, cardioprotectionhttps://www.dovepress.com/cardioprotection-through-pharmacological-activation-of-sirtuin-5-in-a--peer-reviewed-fulltext-article-DDDTSirtuinsSIRT5Myocardial ischemia/reperfusion injurycardioprotection. |
| spellingShingle | Castiello C Efentakis P Nikolaou PE Symeonidi L Chania C Barla I Akrani I Kostomitsopoulos N Gikas E Thomaidis NS Mikros E Kleinbongard P Fioravanti R Zwergel C Valente S Mai A Andreadou I Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction Drug Design, Development and Therapy Sirtuins SIRT5 Myocardial ischemia/reperfusion injury cardioprotection. |
| title | Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction |
| title_full | Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction |
| title_fullStr | Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction |
| title_full_unstemmed | Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction |
| title_short | Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction |
| title_sort | cardioprotection through pharmacological activation of sirtuin 5 in a murine model of acute myocardial infarction |
| topic | Sirtuins SIRT5 Myocardial ischemia/reperfusion injury cardioprotection. |
| url | https://www.dovepress.com/cardioprotection-through-pharmacological-activation-of-sirtuin-5-in-a--peer-reviewed-fulltext-article-DDDT |
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