Urocortin 2 Gene Transfer Reduces the Adverse Effects of a Western Diet on Cardiac Function in Mice.
Urocortin 2 Gene Transfer Reduces the Adverse Effects of a Western Diet on Cardiac Function in Mice.
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尿皮质素 2 基因转移可减少西方饮食对小鼠心脏功能的不利影响。
DOI：
10.1089/hum.2018.150
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发表时间：
2019
影响因子：
4.2
通讯作者：
Hammond,HKirk
中科院分区：
文献类型：
--
作者：
Kim,YoungChul;Giamouridis,Dimosthenis;Lai,NChin;Guo,Tracy;Xia,Bing;Fu,Zhenxing;Gao,MeiHua;Hammond,HKirk
糖尿病与心力衰竭的风险增加有关。先前已经在小鼠中证明，单次注射编码尿皮质素2的腺相关病毒8（AAV8.UCn 2）增加胰岛素抵抗模型中的葡萄糖处置并改善衰竭心脏的功能。本研究验证了UCn 2基因转移可以减轻糖尿病相关的左心室功能障碍的假设。八周龄的C57 BL 6雄性小鼠被喂食西方饮食（WD; 45%脂肪，35%碳水化合物）40周。第30周静脉注射生理盐水或AAV8.UCn2（2 × 1013基因拷贝/kg）。基因转移后10周，通过超声心动图和活体左心室收缩功能测定，测量空腹血糖、葡萄糖耐量和心脏功能，并将结果与正常饲料（NC; 10%脂肪; 70%碳水化合物）喂养的小鼠进行比较。还测量了关键LV信号传导蛋白的含量以探索机制。WD增加12小时空腹血糖（WD：190 ± 11 mg/dL，n= 8; NC：105 ± 12 mg/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）。左心室射血分数无变化。在WD喂养的小鼠中，UCn 2基因转移降低了12小时空腹血糖（WD-UCn 2：149 ± 6 mg/dL，n= 8; WD-生理盐水：190 ± 11 mg/dL，n= 8; p= 0.012），LV峰值+dP/dt增加（p< 0.001）和LV峰值-dP/dt（p= 0.013），并降低Tau（p< 0.02），表明对收缩和舒张LV功能的有益作用。此外，在WD喂养的小鼠中，UCn 2基因转移增加了LV射血分数（p< 0.005）和环周纤维缩短速度（p= 0.0005）。最后，接受UCn 2基因转移的WD喂养小鼠的肝脏脂肪浸润减少。来自WD-UCn 2小鼠的LV样品显示蛋白激酶A催化结构域的磷酸化增加（p= 0.03）。结论：UCn 2基因转移可增加糖尿病相关性左室功能障碍小鼠的左室收缩和舒张功能，降低血糖，提示UCn 2基因转移可能具有潜在的治疗益处。
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.UCn2) increases glucose disposal in models of insulin resistance and improves the function of the failing heart. The present study tested the hypothesis thatUCn2gene 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.UCn2(2 × 1013genome copies/kg) via intravenous injection. Ten weeks after gene transfer, fasting blood glucose, glucose tolerance, and cardiac function were measured via echocardiography andin vivomeasurement 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,n= 8; NC: 105 ± 12 mg/dL,n= 7;p= 0.0004). WD tended to reduce LV peak +dP/dt (p= 0.08) and LV peak –dP/dt (p= 0.05). LV ejection fraction was unchanged. Among WD-fed mice,UCn2gene transfer reduced 12 h fasting glucose (WD-UCn2: 149 ± 6 mg/dL,n= 8; WD-Saline: 190 ± 11 mg/dL,n= 8;p= 0.012), increased LV peak +dP/dt (p< 0.001) and LV peak –dP/dt (p= 0.013), and reduced Tau (p< 0.02), indicating beneficial effects on systolic and diastolic LV function. In addition, among WD-fed mice,UCn2gene transfer increased LV ejection fraction (p< 0.005) and the velocity of circumferential fiber shortening (p= 0.0005). Finally, a reduction was seen in fatty infiltration of the liver in WD-fed mice that had receivedUCn2gene transfer. LV samples from WD-UCn2 mice showed increased phosphorylation of the protein kinase A catalytic domain (p= 0.03). In conclusion,UCn2gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetes-related LV dysfunction, indicating thatUCn2gene transfer may be of potential therapeutic benefit.