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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 
Citation
 BMC MEDICINE, Vol.20(1) : 309, 2022-09 
Journal Title
BMC MEDICINE
Issue Date
2022-09
MeSH
Animals ; Benzhydryl Compounds / pharmacology ; Benzhydryl Compounds / therapeutic use ; Diabetes Mellitus* ; Fibrosis ; Glucosides / pharmacology ; Glucosides / therapeutic use ; Male ; Rabbits ; Sodium-Glucose Transporter 2 Inhibitors* / pharmacology ; Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use
Keywords
Diabetes mellitus ; Heart failure ; Left ventricular diastolic function ; Sodium-glucose cotransporter 2 inhibitor
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.
Files in This Item:
T202203670.pdf Download
DOI
10.1186/s12916-022-02485-z
Appears in Collections:
1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jung Sun(김중선) ORCID logo https://orcid.org/0000-0003-2263-3274
Park, Se Il(박세일) ORCID logo https://orcid.org/0000-0002-4949-8976
Oh, Jae Won(오재원) ORCID logo https://orcid.org/0000-0002-4585-1488
Lee, Seul-Gee(이슬기)
Lee, Seung-Jun(이승준) ORCID logo https://orcid.org/0000-0002-9201-4818
Lee, Oh Hyun(이오현) ORCID logo https://orcid.org/0000-0001-7070-7720
Lee, Yong Joon(이용준)
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Lee, Chan Joo(이찬주) ORCID logo https://orcid.org/0000-0002-8756-409X
Jeon, Ok-Hee(전옥희)
Choi, Dong Hoon(최동훈) ORCID logo https://orcid.org/0000-0002-2009-9760
Hong, Geu Ru(홍그루) ORCID logo https://orcid.org/0000-0003-4981-3304
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/191983
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