Drug Discovery Research, Astellas Pharma Inc.
Biol Pharm Bull. 2022;45(9):1321-1331. doi: 10.1248/bpb.b22-00289.
Evidence from clinical trials suggests that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may arise through non-glycemic control-related mechanisms. Further, the cardiovascular advantages of SGLT2 inhibitors are likely present among non-diabetic patients with known cardiovascular diseases (CVDs). Here, we studied the impact of ipragliflozin, a selective SGLT2 inhibitor, on cardiac histopathology and microRNA (miRNA) expression profiles in a non-diabetic rat model of cardiomyopathy. Ipragliflozin was added to chow (0.01% (w/w)) and given to male DahlS.Z-Lepr/Lepr (DS/obese) rats for 6 weeks. Similarly aged male DahlS.Z-Lepr/Lepr (DS/lean) rats were treated as controls. Measurements of systolic blood pressure (SBP) and heart rate (HR) were taken every other week. Following ipragliflozin treatment for 6 weeks, we conducted echocardiography, histopathological examination, and miRNA expression analysis (microarray). The impact of ipragliflozin on blood parameters was additionally examined. In DS/obese rats, ipragliflozin reduced SBP without affecting HR, reduced interventricular septal thickness in echocardiography and left ventricular (LV) organ weight, and improved hypertrophy of cardiomyocytes according to histopathological experiments. Further, ipragliflozin reduced plasma inflammatory cytokine levels in DS/obese rats. Additionally, ipragliflozin treatment altered the expression profile of miRNAs related to cardiac hypertrophy and heart failure in the LV compared to DS/obese control rats. Ipragliflozin prevented LV hypertrophy and altered related miRNA expression profiles in non-diabetic DS/obese rats. These findings suggest that miRNAs may play a partial role in regulating the structure of the heart and that SGLT2 inhibitors may exert cardio-protective effects by changing miRNA expression profiles in non-diabetic patients with CVDs.
临床试验证据表明，钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂的心脏保护作用可能是通过非血糖控制相关机制产生的。此外，SGLT2 抑制剂在患有已知心血管疾病（CVD）的非糖尿病患者中也可能具有心血管优势。在这里，我们研究了选择性 SGLT2 抑制剂伊格列净对心肌病非糖尿病大鼠模型心脏组织病理学和 microRNA（miRNA）表达谱的影响。伊格列净添加到饲料中（0.01%（w/w）），并给予雄性 DahlS.Z-Lepr/Lepr（DS/肥胖）大鼠 6 周。年龄相同的雄性 DahlS.Z-Lepr/Lepr（DS/瘦）大鼠作为对照进行处理。每隔一周测量一次收缩压（SBP）和心率（HR）。在伊格列净治疗 6 周后，我们进行了超声心动图、组织病理学检查和 miRNA 表达分析（微阵列）。还检查了伊格列净对血液参数的影响。在 DS/肥胖大鼠中，伊格列净降低 SBP 而不影响 HR，在超声心动图中降低室间隔厚度和左心室（LV）器官重量，并根据组织病理学实验改善心肌细胞肥大。此外，伊格列净降低了 DS/肥胖大鼠的血浆炎症细胞因子水平。此外，与 DS/肥胖对照大鼠相比，伊格列净治疗改变了 LV 中与心肌肥大和心力衰竭相关的 miRNA 表达谱。伊格列净预防了非糖尿病 DS/肥胖大鼠的 LV 肥大，并改变了相关的 miRNA 表达谱。这些发现表明，miRNA 可能在调节心脏结构中发挥部分作用，并且 SGLT2 抑制剂可能通过改变非糖尿病 CVD 患者的 miRNA 表达谱来发挥心脏保护作用。
