Effects of Dichloroacetate on the Kv1. 5 of Pulmonary Arterial Smooth Muscle Cells in Simulated High Altitude Pulmonary Hypertension Rats_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

XU Xianhua , PENG Huasheng , SUN Meiqin , WUANG Wanhua , ZHANG Ru , XIAO Xinrong , HU Meng , HU Jian ,  HE Xiaoyin.

Department of Geriatrics,Chengdu Military General Hospital. Sichuan, Chengdu, 610083, ChinaCorresponding Author: XIAO Xin-rong, E-mail: xiaoxinrong1963@ yahoo. com. cn;

Corresponding author：

HE Xiaoyin., Email: xiaoxinrong1963@yahoo.com.cn

Keywords：

High altitude; Hypobaria and hypoxia; Pulmonary artery hypertension; Kv1. 5; Dichloroacetate

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Objective To investigate the role of Kv1. 5 in the pathogenesis of pulmonary hypertension simulated by hypobaria and hypoxia, and the effects of dichloroacetate ( DCA) on the Kv1. 5 expression in pulmonary arterial smooth muscle cells ( PASMCs ) and mean pulmonary arterial pressure ( mPAP) . Methods Twenty-four SD rats were randomly divided into a normal group ( N group) , a high altitude group ( HA group) , and a DCA treated group ( DCA group) . The N group were fed in normal
conditions, the HA group and DCA group were fed in a hypobaria and hypoxia chamber simulated to an altitude of 5000 meters. In addition, the DCA group rats were gastric gavaged with DCA ( 70 mg · kg - 1 · d - 1 ) .Twenty-one days later, percentage of wall thickness ( WT% ) and percentage of wall area ( WA% ) of the pulmonary arteriole, mPAP, and the ratio of right ventricle / left ventricle and septum ( RV/ LV + S) were evaluated. Real-time PCR, immunohistochemistry and Western blot were carried out to detect the Kv1. 5 expression in PASMCs. Results In the HA group, WT% , and WA% of pulmonary arteriole, mPAP and RV/ ( LV + S) all increased significantly compared with the N group ( P lt;0. 01) . These changes in the DCA group were significantly lower than those in the HA group( P lt; 0. 01) . Furthermore, the protein and mRNA expression of Kv1. 5 in the PASMCs deceased significantly in the HA group compared with the N group( P lt;0. 01) , but recovered in the DCA group ( P lt;0. 01) . Conclusions The expression of Kv1. 5 in PASMCs is tremendously inhibited in rats fed in high altitude, which might be a important role of pulmonary
hypertension. DCA can inhibit the remodeling of pulmonary arterials probably by recovering Kv1. 5 expression.

Citation： XU Xianhua,PENG Huasheng,SUN Meiqin,WUANG Wanhua,ZHANG Ru,XIAO Xinrong,HU Meng,HU Jian,HE Xiaoyin.. Effects of Dichloroacetate on the Kv1. 5 of Pulmonary Arterial Smooth Muscle Cells in Simulated High Altitude Pulmonary Hypertension Rats. Chinese Journal of Respiratory and Critical Care Medicine, 2010, 9(1): 53-55. doi: Copy

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.	夏秀琼,程德云,苏巧俐,等.斯伐他汀抑制血管紧张素-Ⅱ受体1的表达,预防大鼠低氧性肺动脉高压.中国呼吸与危重监护杂志,2007,6:213-216.
7.	易群,杨小东,冯玉麟.低氧诱导因子-1β在低氧性肺动脉高压大鼠肺内表达的研究.中国呼吸与危重监护杂志,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. 夏秀琼,程德云,苏巧俐,等.斯伐他汀抑制血管紧张素-Ⅱ受体1的表达,预防大鼠低氧性肺动脉高压.中国呼吸与危重监护杂志,2007,6:213-216.
7. 易群,杨小东,冯玉麟.低氧诱导因子-1β在低氧性肺动脉高压大鼠肺内表达的研究.中国呼吸与危重监护杂志,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.

Chinese Journal of Respiratory and Critical Care Medicine

Effects of Dichloroacetate on the Kv1. 5 of Pulmonary Arterial Smooth Muscle Cells in Simulated High Altitude Pulmonary Hypertension Rats

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