• 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, and Jung-Sun Kim.
• Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
• Bmc Med. 2022 Sep 7; 20 (1): 309309.

BackgroundRecent 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.MethodsA 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).ResultsThe 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.ConclusionsDapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption.© 2022. The Author(s).

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