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Canagliflozin Pretreatment Attenuates Myocardial Dysfunction and Improves Postcardiac Arrest Outcomes After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

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Abstract

Objective

The SGLT2 inhibitor, canagliflozin, not only reduces glycemia in patients with type 2 diabetes but also exerts cardioprotective effects in individuals without diabetes. However, its potential beneficial effects in cardiac arrest have not been characterized. The purpose of this study was to examine the protective effect of canagliflozin pretreatment on postresuscitation-induced cardiac dysfunction in vivo.

Methods

Male C57/BL6 mice were randomized to vehicle (sham and control) or canagliflozin treatment groups. All mice except for the sham-operated mice were subjected to potassium chloride-induced cardiac arrest followed by chest compressions and intravenous epinephrine for resuscitation. Canagliflozin therapy efficacies were evaluated by electrocardiogram, echocardiography, histological analysis, inflammatory response, serum markers of myocardial injury, protein phosphorylation analysis, and immunohistological assessment.

Results

Canagliflozin-pretreated mice exhibited a higher survival rate (P < 0.05), a shorter return of spontaneous circulation (ROSC) time (P < 0.01) and a higher neurological score (P < 0.01 or P < 0.001) than control mice after resuscitation. Canagliflozin was effective at improving cardiac arrest and resuscitation-associated cardiac dysfunction, indicated by increased left ventricular ejection fraction and fractional shortening (P < 0.001). Canagliflozin reduced serum levels of LDH, CK-MB and α-HBDH, ameliorated systemic inflammatory response, and diminished the incidence of early resuscitation-induced arrhythmia. Notably, canagliflozin promoted phosphorylation of cardiac STAT-3 postresuscitation. Furthermore, pharmacological inhibition of STAT-3 by Ag490 blunted STAT-3 phosphorylation and abolished the cardioprotective actions of canagliflozin.

Conclusions

Canagliflozin offered a strong cardioprotective effect against cardiac arrest and resuscitation-induced cardiac dysfunction. This canagliflozin-induced cardioprotection is mediated by the STAT-3-dependent cell-survival signaling pathway.

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Data Availability

All the data in this study are available upon reasonable request from the corresponding author.

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Funding

This study was supported by Grant No. 82270326 (to ZH) from the National Natural Science Foundation of China.

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Authors and Affiliations

  1. Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Feng Ju, Jiaxue Li, Qifeng Wang, Ting Liu, Quanhua Liu & Zhaoyang Hu

  2. Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, USA

    Geoffrey W. Abbott

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  1. Feng Ju
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Contributions

Participated in research design: Zhaoyang Hu.

Conducted experiments and the study: Feng Ju, Jiaxue Li, Qifeng Wang, Ting Liu, Quanhua Liu, Zhaoyang Hu.

Performed data analysis or interpreted the data: Feng Ju, Geoffrey W. Abbott, Jiaxue Li, Qifeng Wang, Ting Liu, Quanhua Liu, Zhaoyang Hu

Wrote or contributed to the writing of the manuscript: Geoffrey W. Abbott, Zhaoyang Hu.

Corresponding author

Correspondence to Zhaoyang Hu.

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Ethics Approval

All animal experiments were conducted in conformity with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (NIH Publication 8th edition, 2011). The experiments were approved by the Institutional Animal Care and Use Committee of Sichuan University (Sichuan, China, approval number: 20211201A).

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Supplementary Information

Supplementary Fig. 1

Ag490 did not affect cardiac morphology or apoptosis (A) Representative H&E-stained heart sections with (+) or without (–) Ag490 after cardiopulmonary resuscitation. Scale bars, 50 μm. n = 5 mice per group. (B) Left Representative TUNEL stained hearts sections with (+) or without (–) Ag490 after cardiopulmonary resuscitation. Scale bars, 50 μm. n = 5 mice per group. Right Apoptotic index in each group. (n = 5 mice per group) (by one-way ANOVA). CON, control. Values for sham, CON, and canagliflozin mice are repeated from Fig. 5B for comparison. (PDF 6100 kb)

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Ju, F., Abbott, G.W., Li, J. et al. Canagliflozin Pretreatment Attenuates Myocardial Dysfunction and Improves Postcardiac Arrest Outcomes After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice. Cardiovasc Drugs Ther 38, 279–295 (2024). https://doi.org/10.1007/s10557-022-07419-8

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