Yonsei Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, South Korea.
Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
BMC Med. 2022 Sep 7;20(1):309. doi: 10.1186/s12916-022-02485-z.
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.
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).
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.
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.
最近的研究报告称，钠-葡萄糖共转运蛋白 2 抑制剂（SGLT2i）可改善舒张功能。我们旨在研究达格列净对糖尿病动物模型左心室（LV）舒张功能的影响，并确定其作用的分子和细胞机制。
共 30 只雄性新西兰白兔随机分为对照组、糖尿病组和糖尿病+达格列净组（每组 n = 10）。通过静脉注射链脲佐菌素诱导糖尿病。使用超声心动图评估心功能。获取心肌样本进行组织学和分子评估。为了进行细胞评估，获得纤维化诱导的心肌细胞（H9C2），并进行转染以进行机制分析（血清和糖皮质激素调节激酶 1（SGK1）信号分析）。
与糖尿病组相比，糖尿病+达格列净组舒张功能障碍减轻。达格列净通过抑制 SGK1 和上皮钠通道（ENaC）蛋白抑制心肌纤维化，这在心肌组织和 H9C2 细胞中均观察到。此外，达格列净具有抗炎作用，并改善了线粒体损伤。siRNA 抑制 SGK1 表达可减少糖尿病+达格列净组的 ENaC 和 Na+/H+交换体 1（NHE1）表达，证实 siSGK1 可显著减少 ENaC 和 NHE1 的表达。
达格列净通过调节 SGK1 信号通路减轻左心室舒张功能障碍和心脏纤维化。达格列净还减少了巨噬细胞和炎症蛋白，并改善了线粒体损伤。
