한빛사논문
- 조회303
Seul‑Gee Lee1†, Darae Kim2†, Jung‑Jae Lee1, Hyun‑Ju Lee3, Ro‑kyung Moon4, Yong‑Joon Lee5, Seung‑Jun Lee5, Oh‑Hyun Lee6, Choongki Kim7, Jaewon Oh5, Chan Joo Lee5, Yong‑ho Lee8, Seil Park9, Ok‑Hee Jeon9, Donghoon Choi6, Geu‑Ru Hong5* and Jung‑Sun Kim5*
1Yonsei Cardiovascular Research Institute, Yonsei University College of Medi‑cine, Seoul, South Korea. 2Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 3Graduate Yonsei University, Seoul, South Korea. 4College of Medicine, Yonsei University Seoul, Seoul, South Korea. 5Division of Cardiol‑ogy, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. 6Division of Cardiology, Yongin Severance Hospital, Yonsei University College of Medicine, Gyeonggi‑do, South Korea. 7Department of Cardiology, Ewha Womans University College of Medicine, Seoul Hospital, Seoul, South Korea. 8Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. 9Cardiovascular Product Evaluation Center, Yonsei University Col‑lege of Medicine, Seoul, South Korea.
†Seul-Gee Lee and Darae Kim have contributed equally to this paper as the frst authors.
*Correspondence
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.
논문정보
- Research article
- 2022년 09월 (BRIC 등록일 2022-10-04)
- 국내 연구진
- 의약학 > 응용의학
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