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BMC Medicine
Published in: BMC Medicine 1/2022

Open Access 01-12-2022 | Dapagliflozin | Research article

Dapagliflozin attenuates diabetes-induced diastolic dysfunction and cardiac fibrosis by regulating SGK1 signaling

Authors: Seul-Gee Lee, Darae Kim, Jung-Jae Lee, Hyun-Ju Lee, Ro-kyung Moon, Yong-Joon Lee, Seung-Jun Lee, Oh-Hyun Lee, Choongki Kim, Jaewon Oh, Chan Joo Lee, Yong-ho Lee, Seil Park, Ok-Hee Jeon, Donghoon Choi, Geu-Ru Hong, Jung-Sun Kim

Published in: BMC Medicine | Issue 1/2022

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Abstract

Background

Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function.

Methods

A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis).

Results

The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group.

Conclusions

Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption.
Appendix
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Metadata
Title
Dapagliflozin attenuates diabetes-induced diastolic dysfunction and cardiac fibrosis by regulating SGK1 signaling
Authors
Seul-Gee Lee
Darae Kim
Jung-Jae Lee
Hyun-Ju Lee
Ro-kyung Moon
Yong-Joon Lee
Seung-Jun Lee
Oh-Hyun Lee
Choongki Kim
Jaewon Oh
Chan Joo Lee
Yong-ho Lee
Seil Park
Ok-Hee Jeon
Donghoon Choi
Geu-Ru Hong
Jung-Sun Kim
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2022
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-022-02485-z

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