二氯醋酸鈉對模擬高原肺動脈高壓大鼠肺動脈平滑肌細胞Kv1.5亞型的作用研究_《中國呼吸與危重監護雜志》

作者：

徐賢華 , 彭華生 , 孫梅芹 , 王萬華 , 張汝 , 胡猛 , 胡健 , 何曉英 ,  肖欣榮

成都軍區總醫院干部病房（四川成都 610083）;

關鍵詞：

高原低壓低氧肺動脈高壓電壓門控性鉀通道Kv1. 5 亞型二氯醋酸鈉

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目的研究電壓門控性鉀通道亞型( Kv1. 5) 在高原低壓低氧性肺動脈高壓中的作用,觀察二氯醋酸鈉( DCA) 對高原低壓低氧性肺動脈高壓大鼠肺小動脈平滑肌細胞( PASMCs) 電壓門控性鉀通道Kv1. 5 亞型基因表達的影響和肺動脈高壓的降壓作用。方法 24 只雄性SD 大鼠隨機分為正常對照組( N組, 8 只) 、高原低壓低氧組( HA 組, 8 只) 及DCA 干預組( DCA 組, 8 只) 。N組置于平原處室內喂養, HA 組和DCA 組均同時置于模擬的海拔5000 m高原環境, DCA 組大鼠予以DCA70 mg·kg- 1·d- 1灌胃。21 d 后測量三組大鼠平均肺動脈壓( mPAP) 、肺小動脈平滑肌和心臟壁厚度, 用熒光定量PCR 法檢測三組大鼠PASMCs Kv1. 5 mRNA, 免疫組織化學和免疫印跡法觀察大鼠PASMCs Kv1. 5 蛋白的表達。結果模擬高原5000 m21 d 后, HA 組大鼠mPAP 明顯高于N組( P lt;0. 01) , 其肺小動脈管壁增厚, 管腔狹窄, 表現為管壁厚度占外徑的百分比( WT%) 、管壁面積占總面
積的百分比( WA%) 和右心室與左心室加室間隔之比( RV/LV +S) 較N組明顯升高( P 均 lt;0. 01) 。與HA 組相比, DCA組mPAP 則明顯降低( P lt; 0. 01) , 表現血管重構減弱, WT%和WA% 明顯下降( P lt; 0. 01) , RV/LV + S下降( P lt; 0. 01) 。HA 組Kv1. 5 mRNA 明顯低于N組( P lt;0. 01) , DCA 組Kv1. 5mRNA 則明顯恢復表達( P lt; 0. 01) 。HA 組肺小動脈壁Kv1. 5 平均光密度低于N組( P lt;0. 01) , DCA 組則明顯高于HA 組( P lt;0. 01) 。蛋白表達呈現相似結果。結論高原低壓低氧性大鼠PASMCs Kv1. 5表達明顯受到抑制, DCA 具有恢復Kv1. 5 表達、阻止肺小動脈重塑及降低肺動脈壓的作用。

引用本文： 徐賢華,彭華生,孫梅芹,王萬華,張汝,胡猛,胡健,何曉英,肖欣榮. 二氯醋酸鈉對模擬高原肺動脈高壓大鼠肺動脈平滑肌細胞Kv1.5亞型的作用研究. 中國呼吸與危重監護雜志, 2010, 9(1): 53-55. doi: 復制

1.	Wang J,Weigand L,Wang W, et al.Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery.Am J Physiol Lung Cell Mol Physiol,2005,288:L1049-L1058.
2.	Pozeg ZI,Michelakis ED,McMurtry MS,et al.In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats.Circulation,2003,107:2037-2044.
3.	Remillard CV,Tigno DD,Platoshyn O,et al.Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension.Am J Physiol Cell Physiol,2007,292:C1837-1853.
4.	Rozanski GJ,Xu Z,Zhang K,et al. Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction.Am J Physiol,1998,274:H259-H265.
5.	Michelakis ED,McMurtry MS,Wu XC,et al.Dichloroacetate,a metabolic modulator,prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels.Circulation,2002,105,244-250.
6.	夏秀瓊,程德云,蘇巧俐,等.斯伐他汀抑制血管緊張素-Ⅱ受體1的表達,預防大鼠低氧性肺動脈高壓.中國呼吸與危重監護雜志,2007,6:213-216.
7.	易群,楊小東,馮玉麟.低氧誘導因子-1β在低氧性肺動脈高壓大鼠肺內表達的研究.中國呼吸與危重監護雜志,2003,2,31-34.
8.	Wang J,Juhaszova M,Rubin LJ,et al.Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells.J Clin Invest,1997,100:2347-2353.
9.	Brevnova EE,Platoshyn O,Zhang S,et al.Overexpression of human KCNA5 increases IK V and enhances apoptosis.Am J Physiol Cell Physiol,2004,287:C715-722.
10.	Stacpoole PW,Nagaraja NV,Hutson AD.Efficacy of dichloroacetate as a lactate-lowering drug.J Clin Pharmacol,2003,43:683-691.
11.	McMurtry MS,Bonnet S,Wu X,et al.Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.Circ Res,2004,95:830-840.

1. Wang J,Weigand L,Wang W, et al.Chronic hypoxia inhibits Kv channel gene expression in rat distal pulmonary artery.Am J Physiol Lung Cell Mol Physiol,2005,288:L1049-L1058.
2. Pozeg ZI,Michelakis ED,McMurtry MS,et al.In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats.Circulation,2003,107:2037-2044.
3. Remillard CV,Tigno DD,Platoshyn O,et al.Function of Kv1.5 channels and genetic variations of KCNA5 in patients with idiopathic pulmonary arterial hypertension.Am J Physiol Cell Physiol,2007,292:C1837-1853.
4. Rozanski GJ,Xu Z,Zhang K,et al. Altered K+ current of ventricular myocytes in rats with chronic myocardial infarction.Am J Physiol,1998,274:H259-H265.
5. Michelakis ED,McMurtry MS,Wu XC,et al.Dichloroacetate,a metabolic modulator,prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels.Circulation,2002,105,244-250.
6. 夏秀瓊,程德云,蘇巧俐,等.斯伐他汀抑制血管緊張素-Ⅱ受體1的表達,預防大鼠低氧性肺動脈高壓.中國呼吸與危重監護雜志,2007,6:213-216.
7. 易群,楊小東,馮玉麟.低氧誘導因子-1β在低氧性肺動脈高壓大鼠肺內表達的研究.中國呼吸與危重監護雜志,2003,2,31-34.
8. Wang J,Juhaszova M,Rubin LJ,et al.Hypoxia inhibits gene expression of voltage-gated K+ channel alpha subunits in pulmonary artery smooth muscle cells.J Clin Invest,1997,100:2347-2353.
9. Brevnova EE,Platoshyn O,Zhang S,et al.Overexpression of human KCNA5 increases IK V and enhances apoptosis.Am J Physiol Cell Physiol,2004,287:C715-722.
10. Stacpoole PW,Nagaraja NV,Hutson AD.Efficacy of dichloroacetate as a lactate-lowering drug.J Clin Pharmacol,2003,43:683-691.
11. McMurtry MS,Bonnet S,Wu X,et al.Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.Circ Res,2004,95:830-840.

《中國呼吸與危重監護雜志》

二氯醋酸鈉對模擬高原肺動脈高壓大鼠肺動脈平滑肌細胞Kv1.5亞型的作用研究

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《中國呼吸與危重監護雜志》

二氯醋酸鈉對模擬高原肺動脈高壓大鼠肺動脈平滑肌細胞Kv1.5亞型的作用研究

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