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Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction

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Titel: Cardioprotection Through Pharmacological Activation of Sirtuin 5 in a Murine Model of Acute Myocardial Infarction
Autoren: Castiello, Carola, Efentakis, Panagiotis, Nikolaou, Panagiota-Efstathia, Symeonidi, Lydia, Chania, Christina, Barla, Ioanna, Akrani, Ifigeneia, Kostomitsopoulos, Nikolaos, Gikas, Evangelos, Thomaidis, Nikolaos, Mikros, Emmanuel, Kleinbongard, Petra, Fioravanti, Rossella, Zwergel, Clemens, Valente, Sergio, Mai, Antonello, Andreadou, Ioanna
Quelle: Drug Des Devel Ther
Drug Design, Development and Therapy, Vol Volume 19, Iss Issue 1, Pp 5489-5505 (2025)
Verlagsinformationen: Informa UK Limited, 2025.
Publikationsjahr: 2025
Schlagwörter: SIRT5, cardioprotection, Sirtuins, Therapeutics. Pharmacology, RM1-950, Myocardial ischemia/reperfusion injury, sirtuins, SIRT5, myocardial ischemia/reperfusion injury, cardioprotection, Original Research
Beschreibung: PURPOSE: 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 μΜ 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 10(th) min of R suggested increased fatty acid oxidation, as indicated by increased N(3)-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.
Publikationsart: Article
Other literature type
Sprache: English
ISSN: 1177-8881
DOI: 10.2147/dddt.s509337
Zugangs-URL: https://doaj.org/article/e2a492bcbf0348a0bba5376bfa2b17a9
https://hdl.handle.net/11573/1742029
https://doi.org/10.2147/dddt.s509337
Rights: CC BY NC
URL: http://creativecommons.org/licenses/by-nc/4.0/This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at http://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0/ (http://creativecommons.org/licenses/by-nc/4.0/) ). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (http://www.dovepress.com/terms.php).
Dokumentencode: edsair.doi.dedup.....ecd438c98f46f6a6bf0dc0f9c89fce7e
Datenbank: OpenAIRE
Beschreibung
Abstract:PURPOSE: 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 μΜ 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 10(th) min of R suggested increased fatty acid oxidation, as indicated by increased N(3)-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.
ISSN:11778881
DOI:10.2147/dddt.s509337