促发低氧性肺动脉高压的新机制——肺微动脉的血管胰岛素敏感性降低及其信号障碍
《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]
- 期数:
- 2014年第3期
- 页码:
- 274-279
- 栏目:
- 基础研究
- 出版日期:
- 2014-03-20
文章信息/Info
- Title:
- A novel pathogenetic mechanism of hypoxic pulmonary hypertension: decreased insulin sensitivity in pulmonary arterial hypertension
- Author(s):
- HE Jin xiao1; FAN Fang 1; XING Wen juan2; LIANG Xiang yan3; JI Le le3; ZHANG Hai feng3; SUN Xin1
- (1.Department of Pediatrics, Xijing Hospital,
2.Department of Physiology,
3.Experiment Teaching Center, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China)
- Keywords:
- hypoxic pulmonary hypertension; vascular insulin resistance; pulmonary microvascular endothelial cells; rat
- 分类号:
- R543.2
- DOI:
- -
- 文献标识码:
- A
- 摘要:
- 目的:观察低氧诱导大鼠肺微血管内皮细胞（PMVEC），是否同样存在肺血管的胰岛素敏感性变化？并探讨潜在的分子机制。方法:采用低压低氧法建立低氧性肺动脉高压（HPH）大鼠模型，14只雄性SD大鼠随机分为：正常对照组和HPH组（低氧4周），每组7只大鼠（n=7）测定两组平均肺动脉压（mPAP）及胰岛素诱导的血管舒张效应。原代培养大鼠PMVEC，分为常氧（21%O2，37℃）和低氧（10%O2，37℃）处理，分别培养6 h、24 h、48 h和96 h收集细胞以Western blot检测Tribbles同源蛋白3（TRB3）、过氧化物酶体增殖物激活受体（PPARγ）及胰岛素的磷脂肌醇3激酶/蛋白激酶B/内皮一氧化氮合酶（PI3K/Akt/eNOS）信号通路蛋白水平，培养基上清检测一氧化氮（NO）生成量。结果:与正常对照组比较，低氧组mPAP明显升高，胰岛素诱导的肺动脉血管舒张作用明显减弱（P<0.05，P<0.01）。PMVEC在含胰岛素的内皮培养基培养不同时间，低氧组与常氧组相比，培养6 h NO量明显升高，培养24 h后有所下降，随低氧时间的延长下降幅度增大（P<0.01）；随低氧时间延长，PI3K-p85、p-Akt、p-eNOS表达逐渐下降，低氧时间越长下降幅度越明显，与NO生成相一致，p-ERK1/2随低氧时间延长表达明显升高；随低氧时间延长TRB3表达增加显著，而PPARγ表达减少（P<0.05，P<0.01）。而不同培养时间常氧组间NO量及上述蛋白表达无显著性差异。结论:低氧可诱导大鼠PMVEC内TRB3的过表达从而负性调控PPARγ，引起下游胰岛素信号通路受损，造成肺血管内皮功能异常，进而促进HPH发生。
- Abstract:
- AIM:To investigate the underlying molecular mechanisms responsible for vascular insulin resistance (VIR) in pulmonary arterial hypertension (PAH). METHODS: Fourteen male Sprague Dawley rats were randomly divided into two groups: normal group and hypoxic pulmonary hypertension (HPH) group (exposed in hypobaric and hypoxia condition for 4 weeks). Pulmonary arterial pressure (PAP) and insulin-induced vasodilation effects of pulmonary artery rings were measured. Primary rat pulmonary microvascular endothelial cells (PMVEC) were cultured, respectively, in normal oxygen (21% O2, 37℃) and low oxygen (10% O2, 37℃) incubators. After cultured at 6, 24, 48, 96 h, cells were collected to detect the expression of TRB3, PPAR-γ and insulin signaling proteins by Western blot. Culture supernatant was used to detect generation of nitric oxide (NO). RESULTS: Compared with those in the control group, mPAP was significantly enhanced in the HPH group, whereas insulin-induced vasorelaxation reaction was significantly attenuated (n=7, P<0.05 of P<0.01). Compared with that in the normoxic group, NO level significantly increased after 6 h, declined after 24 h in the HPH group and further decreased with prolonged hypoxia. Such trends of NO changes were consistent with the expressions of PI3K-p85, p-Akt, p-eNOS but contrary to those of p-ERK1/2. In addition, TRB3 was distinctly overexpressed, whereas PPAR-γ expression decreased. CONCLUSION: Hypoxia induces overexpression of TRB3 in rat PMVEC, which negatively regulates PPAR-γ, leading to the imbalance of insulin signaling pathways and then dysfunction of PMVEC, thus contributing to the development of PHP.
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备注/Memo
- 备注/Memo:
- 收稿日期：2014-01-01.
基金项目：国家自然科学基金项目资助（81270330，30700345，31371151，31271219），陕西省国际合作课题项目资助（2013KW30-02），陕西省科学技术研究发展计划项目资助(2013KJXX-89)
通讯作者：孙新，副教授，主要从事肺动脉高压研究 Email:sunxin6@fmmu.edu.cn
共同通讯作者：张海锋，副教授，主要从事心血管胰岛素抵抗研究 Email:hfzhang@fmmu.edu.cn
作者简介：何金孝，硕士生 Email: hejx_2013@126.com
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