Dipeptidylpeptidase Inhibition Is Associated with Improvement in Blood Pressure and Diastolic Function in Insulin-Resistant Male Zucker Obese Rats
Dipeptidylpeptidase Inhibition Is Associated with Improvement in Blood Pressure and Diastolic Function in Insulin-Resistant Male Zucker Obese Rats
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DOI：
10.1210/en.2013-1096
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发表时间：
2013-07-01
期刊：
影响因子：
4.8
通讯作者：
DeMarco, Vincent G.
中科院分区：
文献类型：
--
作者：
Aroor, Annayya R.;Sowers, James R.;DeMarco, Vincent G.
舒张功能障碍是未来心血管事件的预测指标，与肥胖密切相关。药物抑制二肽基肽酶-4 （DPP-4）以提高胰高血糖素样肽-1的生物利用度是控制2型糖尿病患者血糖的一种新兴疗法。越来越多的证据表明胰高血糖素样肽-1在心血管组织中具有胰岛素不依赖型作用。然而，尚不清楚DPP-4抑制是否能改善肥胖相关的舒张功能障碍。8周龄的Zucker肥胖大鼠（ZO）和Zucker瘦肉大鼠分别饲喂正常饲料或含有DPP-4抑制剂利格列汀（LGT）的饲料8周。与Zucker瘦大鼠相比，ZO的血浆DPP-4活性高3.3倍，LGT处理降低了95%。LGT改善了ZO对照组大鼠受损的超声心动图和压力容积衍生的舒张功能指标，而在研究期间没有改变食物摄入量或体重增加。LGT还能减弱ZO大鼠的血压升高进展，包括改善骨骼肌小动脉功能，但不减少ZO心脏的左心室肥厚、纤维化或氧化应激。磷酸化内皮一氧化氮合酶（eNOS）（Ser1177）、总eNOS和肌浆网钙atp酶2a蛋白的表达在llt处理的ZO心脏中升高，表明Ca2+处理得到改善。ZO心肌线粒体肌体排列和嵴结构异常，经LGT恢复正常。这些研究表明，LGT可以降低血压，改善细胞内Ca-i（2+）处理不当和心肌细胞超微结构，这些共同导致在没有减少左心室肥厚、纤维化或氧化应激的情况下，胰岛素抵抗ZO大鼠的舒张功能改善。
Diastolic dysfunction is a prognosticator for future cardiovascular events that demonstrates a strong correlation with obesity. Pharmacological inhibition of dipeptidylpeptidase-4 (DPP-4) to increase the bioavailability of glucagon-like peptide-1 is an emerging therapy for control of glycemia in type 2 diabetes patients. Accumulating evidence suggests that glucagon-like peptide-1 has insulin-independent actions in cardiovascular tissue. However, it is not known whether DPP-4 inhibition improves obesity-related diastolic dysfunction. Eight-week-old Zucker obese (ZO) and Zucker lean rats were fed normal chow diet or diet containing the DPP-4 inhibitor, linagliptin (LGT), for 8 weeks. Plasma DPP-4 activity was 3.3-fold higher in ZO compared with Zucker lean rats and was reduced by 95% with LGT treatment. LGT improved echocardiographic and pressure volume-derived indices of diastolic function that were impaired in ZO control rats, without altering food intake or body weight gain during the study period. LGT also blunted elevated blood pressure progression in ZO rats involving improved skeletal muscle arteriolar function, without reducing left ventricular hypertrophy, fibrosis, or oxidative stress in ZO hearts. Expression of phosphorylated-endothelial nitric oxide synthase (eNOS)(Ser1177), total eNOS, and sarcoplasmic reticulum calcium ATPase 2a protein was elevated in the LGT-treated ZO heart, suggesting improved Ca2+ handling. The ZO myocardium had an abnormal mitochondrial sarcomeric arrangement and cristae structure that were normalized by LGT. These studies suggest that LGT reduces blood pressure and improves intracellular Ca-i(2+) mishandling and cardiomyocyte ultrastructure, which collectively result in improvements in diastolic function in the absence of reductions in left ventricular hypertrophy, fibrosis, or oxidative stress in insulin-resistant ZO rats.