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- 2017
贝前列素钠对低氧性肺动脉高压大鼠的作用及对肺动脉平滑肌氧敏感性KV通道表达的影响
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Abstract:
摘要：目的 探讨贝前列素钠(BPS)对低氧性肺动脉高压(HPH)大鼠的疗效，及其对肺动脉平滑肌氧敏感性KV通道表达的影响。方法 采用在低压低氧舱内每日饲养8h的方法建立HPH大鼠模型；BPS干预组每日给予BPS灌胃[300μg/(kg？d)]，对照组和模型组给予生理盐水灌胃；4周后测定平均肺动脉压力(mPAP)，计算右心肥厚指数(RVHI)，肺组织切片HE染色评价肺动脉壁增厚程度，Real-time PCR和Western blot检测肺小动脉平滑肌KV1.2、KV1.5、KV2.1 mRNA和蛋白表达水平。结果 连续4周低压低氧成功诱导HPH大鼠模型；与模型组相比，BPS干预后mPAP和RVHI降低[mPAP：(13.48±2.18)mmHg vs. (23.87±2.23)mmHg vs. (17.09±1.20)mmHg；RVHI：0.28±0.02 vs. 0.46±0.03 vs. 0.36±0.04；P<0.05]；肺小动脉重构改善(中膜面积百分比：35.72±6.58 vs. 68.52±5.64 vs. 46.58±8.43，P<0.05)，肺动脉平滑肌KV1.2、KV1.5、KV2.1 mRNA和蛋白表达水平升高(蛋白相对表达量：KV1.2，0.78±0.10 vs.0.15±0.03 vs. 0.57±0.13；KV1.5，0.61±0.10 vs. 0.31±0.05 vs. 0.59±0.13；KV2.1，0.29±0.05 vs. 0.10±0.02 vs. 0.28±0.07；P<0.05)。 结论 BPS可改善HPH大鼠的肺动脉高压，并上调肺动脉平滑肌KV1.2、KV1.5、KV2.1的表达。
ABSTRACT: Objective?? To explore the effect of beraprost sodium (BPS) on hypoxia-induced pulmonary artery hypertension (HPH) in rats and the expression of oxygen-sensitive KV channels in pulmonary artery smooth muscle (PASM). Methods?? The HPH model of rats was established by exposing rats to low-pressure and low-oxygen cabin which was auto-modulated for 8h every day. Rats in the BPS group were given an intragastric administration of BPS [300μg/(kg？d)], while those in the control group and HPH group were given an intragastric administration of 3ml/kg of 0.9% saline. After 4 weeks, the mean pulmonary artery pressure (mPAP) was measured and right heart ventricle hypertrophy index (RVHI) was calculated; pulmonary artery remodeling was evaluated by HE staining; the expressions of KV1.2, KV1.5 and KV2.1 in the pulmonary artery were detected by Real-time PCR and Western blot. Results The HPH model was successfully established in rats exposed to chronic hypoxia for 4 weeks. Compared with those in HPH group, mPAP, RVHI and pulmonary artery remodeling were decreased in BPS group [mPAP: (13.48±2.18)mmHg vs. (23.87±2.23)mmHg vs. (17.09±1.20)mmHg; RVHI: 0.28±0.02 vs. 0.46±0.03 vs. 0.36±0.04; % area of medial smooth muscle: 35.72±6.58 vs. 68.52±5.64 vs. 46.58±8.43; P<0.05], and the mRNA and protein expressions of KV1.2, KV1.5 and KV2.1 were increased (relative protein expression level: KV1.2, 0.78±0.10 vs. 0.15±0.03 vs. 0.57±0.13；KV1.5, 0.61±0.10 vs. 0.31±0.05 vs. 0.59±0.13; KV2.1, 0.29±0.05 vs. 0.10±0.02 vs. 0.28±0.07; P<0.05). Conclusion?? BPS can improve pulmonary arterial hypertension induced by hypoxia, and upregulate the decreased mRNA and protein expressions of KV1.2, KV1.5 and KV2.1 in pulmonary artery
| [1] | SOMMER N, STRIELKOV I, PAK O, et al. Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction[J]. Eur Res J, 2016, 47(1):288-303. |
| [2] | PLATOSHYN O, YU Y, GOLOVINA VA, et al. Chronic hypoxia decreases Kv channel expression and function in pulmonary artery myocytes[J]. Am J Physiol Lung Cell Mol Physiol, 2001, 280(4):L801-812. |
| [3] | WEIR EK, OLSCHEWSKI A. Role of ion channels in acute and chronic responses of the pulmonary vasculature to hypoxia[J]. Cardiovasc Res, 2006, 71(4):630-641. |
| [4] | BURG ED, REMILLARD CV, YUAN JX. Potassium channels in the regulation of pulmonary artery smooth muscle cell proliferation and apoptosis: Pharmacotherapeutic implications[J]. Br J Pharmacol, 2008, 153:S99-S111. |
| [5] | MORRELL ED, TSAI BM, CRISOSTOMO PR, et al. Therapeutic concepts for hypoxic pulmonary vasocons-triction involving ion regulation and the smooth muscle contractile apparatus[J]. J Mol Cell Cardiol, 2006, 40(6):751-760. |
| [6] | GALI？K N, HUMBERT M, VACHIERY JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension[J]. Eur Heart J, 2016, 37(1):67-119. |
| [7] | 李娟，孙新，毕辉，等. 低压低氧性大鼠肺动脉高压模型的建立[J]. 临床心血管病杂志, 2008, 24(4):297-301. |
| [8] | STENMARK KR, FAGAN KA, FRID MG. Hypoxia-induced pulmonary vascular remodeling: Cellular and molecular mechanisms[J]. Circ Res, 2006, 99(7):675-691. |
| [9] | TUDER RM, COOL CD, GERACI MW, et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension[J]. Am J Respir Crit Care Med, 1999, 159(6):1952-1932. |
| [10] | CHRISTMAN BW, MCPHERSON CD, NEWMAN JH, et al. An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension[J]. N Engl J Med, 1992, 327(2):70-75. |
| [11] | GALIE？K N, HUMBERT M, VACHI？IRY JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension a randomized, double blind placebo controlled trial[J]. J Am Coll Cardiol, 2002, 39(9):1496-1502. |
| [12] | FAN FL, MA AQ, GUAN YF, et al. Effect of PGE2 on DA tone by EP4 modulating Kv channels with different oxygen tension between preterm and term[J]. Int J Cardiol, 2011, 147(1):58-65. |
| [13] | SAKAO S, TANABE N, KASAHARA Y, et al. Long-term survival of Japanese patients with pulmonary arterial hypertension treated with beraprost sodium, an oral prostacyclin analogue[J]. Intern Med, 2014, 53(17):1913-1920. |
| [14] | SWEENEY M, YUAN JX. Hypoxic pulmonary vasoconstriction: Role of voltagegated potassium channels[J]. Respir Res, 2000, 1(1):40-48. |
| [15] | WANG J, WEIGAND L, WANG WQ, et al. Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery[J]. Am J Physiol Lung Cell Mol Physiol, 2005, 288(6):L1049-L1058. |
| [16] | BARST RJ, MCGOON M, MCLAUGHLIN V, et al. Beraprost therapy for pulmonary arterial hypertension[J]. J Am Coll Cardial, 2003, 41(12):2119-2125. |
| [17] | LAI YJ, PULLAMSETTI SS, DONY E, et al. Role of the prostanoid EP4 receptor in iloprost-mediated vasodilatation in pulmonary hypertension[J]. Am J Respir Crit Care Med, 2008, 178(2):188-196. |
| [18] | FRUMKIN LR. The pharmacological treatment of pulmonary arterial hypertension[J]. Pharmacol Rev, 2012, 64(3):583-620. |
| [19] | GALI？K N, CORRIS PA, FROST A, et al. Updated treatment algorithm of pulmonary arterial hypertension[J]. J Am Coll Cardiol, 2013, 62(25):D60-D72. |
