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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?

Basic Research in Cardiology Aims and scope Submit manuscript

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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Data availability

The raw data of the proteomic analysis are available on MassIVE (Mass Spectrometry Interactive Virtual Environment) open access repository (https://nam12.safelinks.protection.outlook.com/?url=https%3A%2F%2Fmassive.ucsd.edu%2FProteoSAFe%2Fstatic%2Fmassive.jsp&data=05%7C01%7C%7C8b8c34b613694856e07408da31b0984d%7C84df9e7fe9f640afb435aaaaaaaaaaaa%7C1%7C0%7C637876931776087874%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=1im%2BYkixzq8HR%2BsMeGeC2IOkmMWzfL9wuJ38pUx60R0%3D&reserved=0) with the Dataset Identifier: MSV000088582.

Abbreviations

AmR:

Amplex red

Bax:

Apoptosis regulator Bax

Bcl-xL:

B-cell lymphoma-extra large

BIOPS:

Biopsy preservation solution

CANA:

Canagliflozin

Catr:

Carboxyatractyloside

Cav-3:

Caveolin-3

CT-1:

Cardiotrophin-1

CVOTs:

Cardiovascular outcome clinical trials

CCCP:

Carbonyl cyanide 3-chlorophenylhydrazone

DAPA:

Dapagliflozin

eNOS:

Endothelial nitric oxide synthase

EMPA:

Empagliflozin

ETS:

Electron transfer system

ERTU:

Ertugliflozin

FDR:

False discovery rate

FAO:

Fatty acid oxidation

FCR:

Flux control ratio

FGF-2:

Fibroblast growth factor-2

GLUT1 or GLUT 4:

Glucose transporter 1 or 4

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GSK3β:

Glycogen synthase kinase 3 beta

HRP:

Horse radish peroxidase

IS:

Infarct size

IGF-I:

Insulin-like growth factor I

IRI:

Ischemia reperfusion injury

LAD:

Left anterior descending coronary artery

LC/MS–MS:

Liquid chromatography with tandem–mass spectrometry analysis

MACE:

Major adverse cardiovascular events

OXPHOS:

Oxidative phosphorylation

NF-kB:

Nuclear factor kappa B p65

PLS-DA:

Partial least squares-discriminant analysis

PI3K:

Phosphoinositide 3-kinase p85

Akt:

Phospho-protein kinase B

PVDF:

Polyvinylidene difluoride membrane

PKA C-a:

Protein kinase A C-alpha

STAT-3:

Signal transducer and activator of transcription- 3

SGLT-2:

Sodium glucose co-transporter-2

SGLT-2i:

Sodium glucose co-transporter-2 inhibitors

SOTA:

Sotagliflozin

TTC:

Triphenyl-tetrazolium chloride

T2DM:

Type 2 diabetes mellitus

UV:

Unit-Variance

UA buffer:

Urea buffer

VASP:

Vasodilator-stimulated protein

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Acknowledgements

This work has been supported by the EU-CARDIOPROTECTION COST-Action (CA16225). We would like to acknowledge the Hellenic Diabetes Association and the Hellenic Society of Cardiology for the support of this study.

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Nikolaou, P.E., Mylonas, N., Makridakis, M. et al. Cardioprotection by selective SGLT-2 inhibitors in a non-diabetic mouse model of myocardial ischemia/reperfusion injury: a class or a drug effect?. Basic Res Cardiol 117, 27 (2022). https://doi.org/10.1007/s00395-022-00934-7

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