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.
参考文献/References
[1]Galiè N,Hoeper MM,Humbert M,et al.Pulmonary Hypertension (Guidelines on Diagnosis and Treatment of)[J].Eur Heart J,2009,30(20):2493-2537.
[2]程显声.肺动脉高压患者的希望之路——进一步提高肺动脉高压的治疗水平[J].中国处方药,2006,53(8):5-6.
[3]Kim JA,Koh KK,Quon MJ,et al.The union of vascular and metabolic actions of insuli-n in sickness and in health[J].Arterioscler Thromb Vasc Biol,2005,25(5):889-891.
[4]Xing W,Yan W,Liu P,et al.A novel mechanism for vascular insulin resistance in normotensive young SHRs:hypoadiponectinemia and resultant APPL1 downregulation[J].Hypertension,2013,61(5):1028-1035.
[5]Xing W,Li Y,Zhang H,et al.Improvement of vascular insulin sensitivity by downre-gulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats[J].Am J Physiol Heart Circ Physiol,2013,305(8):H1111-H1119.
[6]Li R,Zhang H,Wang W,et al.Vascular insulin esistance in prehypertensive rats:Role of PI3-kinase/Akt/eNOS signaling[J].Eur J Pharmacol,2010,628(1-3):140-147.
[7]范 芳,王 浩,李 浩,等.肺动脉胰岛素敏感性减弱在低氧性肺动脉高压发生中的作用[J].心脏杂志,2013,25(3):296-300.
[8]徐顺贵,吴国明,徐 智,等.组织块法培养大鼠肺微血管内皮细胞的综合鉴定[J].第三军医大学学报,2007,29(1):39-42.
[9]李颖川,江 伟,周 明,等.大鼠肺微血管内皮细胞原代培养方法的改进及细胞鉴定[J].上海交通大学学报,2010,11(30):1440-1443.
[10]De Boer MP,Meijer RI,Wijnstok NJ,et al.Microvascular Dysfunction:A Potential Mechani-sm in the Pathogenesis of Obesity-associated Insulin Resistance and Hypertension[J].Microcirculation,2012,19(1):5-18.
[11]Ko SH,Cao W,Liu Z.Hypertension Management and Microvascular Insulin Resistance in Diabetes[J].Curr Hypertens Rep,2010,12(4):243-251.
[12]Ameshima S,Golpon H,Cool CD,et al.Peroxisome proliferator activated receptor gamma(PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth[J].Circ Res,2003,29(10):1162-1169.
[13]Zhang W,Fu F,Tie R,et al.Alpha-linolenic acid intake prevents endothelial dysfunct-ion in high-fat diet-fed streptozotocin rats and underlying mechanisms[J].Vasa,2013,42(6):421-728.
[14]Zhang W,Li R,Li J,et al.Alphalinolenic acid exerts an endothelial protective effect against high glucose injury via PI3K/Akt pathway[J].PLoS One,2013,8(7):e68489.
[15]Hansmann G,Wagnetr RA,Schellong S,et al.Pulmonary arterial hypertension is linked to insulin resistance and revesed by peroxisome proiiferator-activated receptor gamma activation[J].Circulation, 2001,115(10):1275-1284.
[16]Ti Y,Xie GL,Wang ZH,et al.TRB3 Gene Silencing Alleviates Diabetic Cardiomyopathy in a Type 2 Diabetic Rat Model[J].Diabetic,2011,60(11):294-2974.
[17]Takahashi Y,Nobumichi O,Hidetoshi H,et al.TRB3 suppresses adipocyte differentiation by negatively regulating PPARg transcriptional activity[J].J Lipid Res,2008,49(4):880-892.
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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