Hypoxia-induced pulmonary hypertension in type 2 diabetic mice.
Hypoxia-induced pulmonary hypertension in type 2 diabetic mice.
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DOI：
10.1086/690206
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发表时间：
2017-03
影响因子：
2.6
通讯作者：
Makino A
中科院分区：
文献类型：
--
作者：
Pan M;Han Y;Si R;Guo R;Desai A;Makino A
低氧性肺动脉高压（HPH）是一种主要由慢性暴露于高海拔环境、慢性阻塞性肺疾病和阻塞性睡眠呼吸暂停引起的进行性疾病。肺血管阻力增加和肺动脉压升高导致右心室后负荷增加，导致右心衰和发病率增加。有一些临床报告表明PH值与糖尿病、胰岛素抵抗或肥胖之间存在联系；然而，目前尚不清楚HPH是否作为糖尿病的进行性并发症与糖尿病有关。本研究的主要目的是研究糖尿病“预处理”或启动效应对HPH进展的影响，并确定糖尿病和HPH之间联系的分子机制。我们的数据显示，糖尿病小鼠的HPH显著增强，而慢性缺氧糖尿病小鼠（DH）的肺动脉内皮依赖性松弛明显减弱。此外，我们证明从DH小鼠分离的小鼠肺内皮细胞（mpec）表现出线粒体活性氧（ROS）浓度显著增加和SOD2蛋白表达降低。最后，通过mitoTempol清除线粒体ROS可以恢复DH小鼠肺动脉内皮依赖性松弛。这些数据表明，糖尿病mpec中过量的线粒体ROS产生导致缺氧暴露的糖尿病小鼠发生严重的HPH。
Hypoxia-induced pulmonary hypertension (HPH) is a progressive disease that is mainly caused by chronic exposure to high altitude, chronic obstructive lung disease, and obstructive sleep apnea. The increased pulmonary vascular resistance and increased pulmonary arterial pressure result in increased right ventricular afterload, leading to right heart failure and increased morbidity. There are several clinical reports suggesting a link between PH and diabetes, insulin resistance, or obesity; however, it is unclear whether HPH is associated with diabetes as a progressive complication in diabetes. The major goal of this study is to examine the effect of diabetic “preconditioning” or priming effect on the progression of HPH and define the molecular mechanisms that explain the link between diabetes and HPH. Our data show that HPH is significantly enhanced in diabetic mice, while endothelium-dependent relaxation in pulmonary arteries is significantly attenuated in chronically hypoxic diabetic mice (DH). In addition, we demonstrate that mouse pulmonary endothelial cells (MPECs) isolated from DH mice exhibit a significant increase in mitochondrial reactive oxygen species (ROS) concentration and decreased SOD2 protein expression. Finally, scavenging mitochondrial ROS by mitoTempol restores endothelium-dependent relaxation in pulmonary arteries that is attenuated in DH mice. These data suggest that excessive mitochondrial ROS production in diabetic MPECs leads to the development of severe HPH in diabetic mice exposed to hypoxia.