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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 4/2022

22-04-2021 | Empagliflozin | Original Article

Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy

Authors: Veera Ganesh Yerra, Sri Nagarjun Batchu, Golam Kabir, Suzanne L. Advani, Youan Liu, Ferhan S. Siddiqi, Kim A. Connelly, Andrew Advani

Published in: Cardiovascular Drugs and Therapy | Issue 4/2022

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Abstract

Purpose

Although the cardioprotective benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors are now widely appreciated, the mechanisms underlying these benefits remain unresolved. Tumor necrosis factor receptor superfamily member 12a (Tnfrsf12a) is a receptor for tumor necrosis factor superfamily member 12 (Tnfsf12). Tnfrsf12a is highly inducible and plays a key role in the development of cardiac hypertrophy and heart failure. Here we set out to determine if SGLT2 inhibition affects the Tnfsf12/Tnfrsf12a system in the stressed myocardium.

Methods

C57BL/6N mice that had undergone sham or transverse aortic constriction (TAC) surgery were treated with either the SGLT2 inhibitor empagliflozin (400 mg/kg diet; 60–65 mg/kg/day) or standard chow alone and were followed for 8 weeks. Tnfrsf12a expression in mouse hearts was assessed by in situ hybridization, qRT-PCR, and immunoblotting.

Results

Left ventricular (LV) mass, end-systolic volume, and end-diastolic volume were all increased in TAC mice and were significantly lower with empagliflozin. Myocyte hypertrophy and interstitial fibrosis in TAC hearts were similarly attenuated with empagliflozin. Tnfrsf12a expression was upregulated in mouse hearts following TAC surgery but not in the hearts of empagliflozin-treated mice. In cultured cardiomyocytes, Tnfrsf12a antagonism attenuated the increase in cardiomyocyte size that was induced by phenylephrine.

Conclusion

Empagliflozin attenuates LV enlargement in mice with hypertrophic heart failure. This effect may be mediated, at least in part, by a reduction in loading conditions which limits upregulation of the inducible, proinflammatory, and prohypertrophic TNF superfamily receptor, Tnfrsf12a. Disruption of the Tnfsf12/Tnfrsf12a feed forward system may contribute to the cardioprotective benefits of SGLT2 inhibition.

Graphical abstract

Appendix
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Metadata
Title
Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy
Authors
Veera Ganesh Yerra
Sri Nagarjun Batchu
Golam Kabir
Suzanne L. Advani
Youan Liu
Ferhan S. Siddiqi
Kim A. Connelly
Andrew Advani
Publication date
22-04-2021
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 4/2022
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07190-2

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