1 Veterans Affairs San Diego Healthcare System, San Diego, California.
2 Department of Medicine, University of California San Diego, San Diego, California.
Hum Gene Ther. 2019 Jun;30(6):693-701. doi: 10.1089/hum.2018.150. Epub 2019 Mar 11.
Diabetes mellitus is associated with increased risk of heart failure. It has been previously demonstrated in mice that a single injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.) increases glucose disposal in models of insulin resistance and improves the function of the failing heart. The present study tested the hypothesis that gene transfer would reduce diabetes-related left ventricular (LV) dysfunction. Eight-week-old C57BL6 male mice were fed a Western diet (WD; 45% fat, 35% carbohydrate) for 40 weeks. At week 30, they received saline or AAV8. (2 × 10 genome copies/kg) via intravenous injection. Ten weeks after gene transfer, fasting blood glucose, glucose tolerance, and cardiac function were measured via echocardiography and measurement of LV contractile function, and the results were compared to those of mice fed normal chow (NC; 10% fat; 70% carbohydrate). The contents of key LV signaling proteins were also measured to probe mechanisms. WD increased 12 h fasting glucose (WD: 190 ± 11 mg/dL, = 8; NC: 105 ± 12 mg/dL, = 7; = 0.0004). WD tended to reduce LV peak +dP/dt ( = 0.08) and LV peak -dP/dt ( = 0.05). LV ejection fraction was unchanged. Among WD-fed mice, gene transfer reduced 12 h fasting glucose (WD-UCn2: 149 ± 6 mg/dL, = 8; WD-Saline: 190 ± 11 mg/dL, = 8; = 0.012), increased LV peak +dP/dt ( < 0.001) and LV peak -dP/dt ( = 0.013), and reduced Tau ( < 0.02), indicating beneficial effects on systolic and diastolic LV function. In addition, among WD-fed mice, gene transfer increased LV ejection fraction ( < 0.005) and the velocity of circumferential fiber shortening ( = 0.0005). Finally, a reduction was seen in fatty infiltration of the liver in WD-fed mice that had received gene transfer. LV samples from WD-UCn2 mice showed increased phosphorylation of the protein kinase A catalytic domain ( = 0.03). In conclusion, gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetes-related LV dysfunction, indicating that gene transfer may be of potential therapeutic benefit.
糖尿病与心力衰竭风险增加有关。先前在小鼠中已经证明，单次注射腺相关病毒 8 编码的尿皮质素 2（AAV8）可增加胰岛素抵抗模型中的葡萄糖摄取，并改善衰竭心脏的功能。本研究检验了基因转移将减少与糖尿病相关的左心室（LV）功能障碍的假设。将 8 周龄的 C57BL6 雄性小鼠用西方饮食（WD；45%脂肪，35%碳水化合物）喂养 40 周。在第 30 周，它们通过静脉内注射接受生理盐水或 AAV8。（2×10 基因组拷贝/千克）。基因转移后 10 周，通过超声心动图和 LV 收缩功能测量来测量空腹血糖、葡萄糖耐量和心功能，并将结果与喂食正常饲料（NC；10%脂肪；70%碳水化合物）的小鼠进行比较。还测量了关键的 LV 信号蛋白的含量，以探究机制。WD 增加了 12 小时空腹血糖（WD：190±11mg/dL，n=8；NC：105±12mg/dL，n=7；P=0.0004）。WD 倾向于降低 LV 峰值+dP/dt（P=0.08）和 LV 峰值-dP/dt（P=0.05）。LV 射血分数保持不变。在 WD 喂养的小鼠中，基因转移降低了 12 小时空腹血糖（WD-UCn2：149±6mg/dL，n=8；WD-生理盐水：190±11mg/dL，n=8；P=0.012），增加了 LV 峰值+dP/dt（P<0.001）和 LV 峰值-dP/dt（P=0.013），并降低了 Tau（P<0.02），表明对收缩和舒张 LV 功能有有益作用。此外，在 WD 喂养的小鼠中，基因转移增加了 LV 射血分数（P<0.005）和圆周纤维缩短速度（P=0.0005）。最后，接受基因转移的 WD 喂养小鼠的肝脏脂肪浸润减少。WD-UCn2 小鼠的 LV 样本显示蛋白激酶 A 催化结构域磷酸化增加（P=0.03）。总之，基因转移增加了与糖尿病相关的 LV 功能障碍小鼠的 LV 收缩和舒张功能，并降低了血糖，表明基因转移可能具有潜在的治疗益处。
