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01.12.2022 | Original Contribution

Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?

verfasst von: Panagiota Efstathia Nikolaou, Nikolaos Mylonas, Manousos Makridakis, Marina Makrecka-Kuka, Aikaterini Iliou, Stelios Zerikiotis, Panagiotis Efentakis, Stavros Kampoukos, Nikolaos Kostomitsopoulos, Reinis Vilskersts, Ignatios Ikonomidis, Vaia Lambadiari, Coert J. Zuurbier, Agnieszka Latosinska, Antonia Vlahou, George Dimitriadis, Efstathios K. Iliodromitis, Ioanna Andreadou

Erschienen in: Basic Research in Cardiology | Ausgabe 1/2022

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Abstract

Major clinical trials with sodium glucose co-transporter-2 inhibitors (SGLT-2i) exhibit protective effects against heart failure events, whereas inconsistencies regarding the cardiovascular death outcomes are observed. Therefore, we aimed to compare the selective SGLT-2i empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) in terms of infarct size (IS) reduction and to reveal the cardioprotective mechanism in healthy non-diabetic mice. C57BL/6 mice randomly received vehicle, EMPA (10 mg/kg/day) and DAPA or ERTU orally at the stoichiometrically equivalent dose (SED) for 7 days. 24 h-glucose urinary excretion was determined to verify SGLT-2 inhibition. IS of the region at risk was measured after 30 min ischemia (I), and 120 min reperfusion (R). In a second series, the ischemic myocardium was collected (10th min of R) for shotgun proteomics and evaluation of the cardioprotective signaling. In a third series, we evaluated the oxidative phosphorylation capacity (OXPHOS) and the mitochondrial fatty acid oxidation capacity by measuring the respiratory rates. Finally, Stattic, the STAT-3 inhibitor and wortmannin were administered in both EMPA and DAPA groups to establish causal relationships in the mechanism of protection. EMPA, DAPA and ERTU at the SED led to similar SGLT-2 inhibition as inferred by the significant increase in glucose excretion. EMPA and DAPA but not ERTU reduced IS. EMPA preserved mitochondrial functionality in complex I&II linked oxidative phosphorylation. EMPA and DAPA treatment led to NF-kB, RISK, STAT-3 activation and the downstream apoptosis reduction coinciding with IS reduction. Stattic and wortmannin attenuated the cardioprotection afforded by EMPA and DAPA. Among several upstream mediators, fibroblast growth factor-2 (FGF-2) and caveolin-3 were increased by EMPA and DAPA treatment. ERTU reduced IS only when given at the double dose of the SED (20 mg/kg/day). Short-term EMPA and DAPA, but not ERTU administration at the SED reduce IS in healthy non-diabetic mice. Cardioprotection is not correlated to SGLT-2 inhibition, is STAT-3 and PI3K dependent and associated with increased FGF-2 and Cav-3 expression.

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Titel: Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?
verfasst von: Panagiota Efstathia Nikolaou
Nikolaos Mylonas
Manousos Makridakis
Marina Makrecka-Kuka
Aikaterini Iliou
Stelios Zerikiotis
Panagiotis Efentakis
Stavros Kampoukos
Nikolaos Kostomitsopoulos
Reinis Vilskersts
Ignatios Ikonomidis
Vaia Lambadiari
Coert J. Zuurbier
Agnieszka Latosinska
Antonia Vlahou
George Dimitriadis
Efstathios K. Iliodromitis
Ioanna Andreadou
Publikationsdatum: 01.12.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology / Ausgabe 1/2022
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-022-00934-7

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Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?

Abstract

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