Phosphodiesterase 10A upregulation contributes to pulmonary vascular remodeling.
Phosphodiesterase 10A upregulation contributes to pulmonary vascular remodeling.
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DOI：
10.1371/journal.pone.0018136
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发表时间：
2011-04-11
期刊：
影响因子：
3.7
通讯作者：
Pullamsetti SS
中科院分区：
文献类型：
--
作者：
Tian X;Vroom C;Ghofrani HA;Weissmann N;Bieniek E;Grimminger F;Seeger W;Schermuly RT;Pullamsetti SS
磷酸二酯酶（PDE）通过水解cAMP和cGMP调节参与肺动脉高压（PH）病理生理的细胞增殖。本研究旨在确定最近发现的PDE是否PDE 7-PDE 11参与PH中进行性肺血管重构。所有体外实验均使用从对照大鼠或野百合碱（MCT）诱导的肺动脉高压（MCT-PH）大鼠获得的肺组织或肺动脉平滑肌细胞（PASMC）进行，我们检测了PDE 10抑制剂罂粟碱（Pap）和特异性小干扰RNA（siRNA）的作用。此外，从第21天至第35天通过连续静脉输注向MCT诱导的PH大鼠给予罂粟碱，以检查PDE 10A抑制的体内效应。我们发现PDE 10A主要存在于肺血管中，与对照PASMCs相比，MCT PASMCs中PDE 10A的mRNA、蛋白和活性水平均显著升高。罂粟碱和PDE 10A siRNA诱导细胞内cAMP的积累，激活cAMP反应元件结合蛋白并减弱PASMC增殖。在MCT-PH大鼠中静脉输注罂粟碱导致对肺动脉高压血流动力学参数和肺血管重构的影响减弱40%-50%。本研究首次证明了PDE 10A在进行性肺血管重构中的核心作用，结果表明了治疗PH的新治疗方法。
Phosphodiesterases (PDEs) modulate the cellular proliferation involved in the pathophysiology of pulmonary hypertension (PH) by hydrolyzing cAMP and cGMP. The present study was designed to determine whether any of the recently identified PDEs (PDE7-PDE11) contribute to progressive pulmonary vascular remodeling in PH. All in vitro experiments were performed with lung tissue or pulmonary arterial smooth muscle cells (PASMCs) obtained from control rats or monocrotaline (MCT)-induced pulmonary hypertensive (MCT-PH) rats, and we examined the effects of the PDE10 inhibitor papaverine (Pap) and specific small interfering RNA (siRNA). In addition, papaverine was administrated to MCT-induced PH rats from day 21 to day 35 by continuous intravenous infusion to examine the in vivo effects of PDE10A inhibition. We found that PDE10A was predominantly present in the lung vasculature, and the mRNA, protein, and activity levels of PDE10A were all significantly increased in MCT PASMCs compared with control PASMCs. Papaverine and PDE10A siRNA induced an accumulation of intracellular cAMP, activated cAMP response element binding protein and attenuated PASMC proliferation. Intravenous infusion of papaverine in MCT-PH rats resulted in a 40%–50% attenuation of the effects on pulmonary hypertensive hemodynamic parameters and pulmonary vascular remodeling. The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling, and the results suggest a novel therapeutic approach for the treatment of PH.
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影响因子：
158.5
作者：
Galiè, N;Ghofrani, HA;Simonneau, G
通讯作者：
Simonneau, G
影响因子：
15.9
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Izikki, Mohamed;Guignabert, Christophe;Eddahibi, Saadia
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Eddahibi, Saadia
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37.8
作者：
Merklinger, SL;Jones, PL;Rabinovitch, M
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Rabinovitch, M
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AOKI, H;NISHIMURA, J;KANAIDE, H
通讯作者：
KANAIDE, H
影响因子：
24.3
作者：
Dahal, B. K.;Kosanovic, D.;Schermuly, R. T.
通讯作者：
Schermuly, R. T.