Phosphodiesterase 10A Upregulation Contributes to Pulmonary Vascular Remodeling

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.磷酸二酯酶（Phosphodiesterases, PDEs）可通过水解环磷酸腺苷（cAMP）与环磷酸鸟苷（cGMP），调控肺动脉高压（pulmonary hypertension, PH）病理生理过程中涉及的细胞增殖。本研究旨在明确新近鉴定的PDE家族成员（PDE7~PDE11）是否参与肺动脉高压的进行性肺血管重构。所有体外实验均采用对照大鼠或野百合碱（monocrotaline, MCT）诱导的肺动脉高压（MCT-PH）大鼠的肺组织或肺动脉平滑肌细胞（pulmonary arterial smooth muscle cells, PASMCs）开展，并检测了PDE10抑制剂罂粟碱（papaverine, Pap）以及特异性小干扰RNA（small interfering RNA, siRNA）的干预效果。此外，本研究于造模后第21天至第35天通过持续静脉输注方式给予MCT诱导的肺动脉高压大鼠罂粟碱，以探究PDE10A抑制的体内效应。研究结果显示，PDE10A主要表达于肺血管系统；与对照大鼠的PASMCs相比，MCT处理组PASMCs中PDE10A的mRNA、蛋白表达水平及酶活性均显著升高。罂粟碱与PDE10A siRNA可诱导细胞内cAMP积累，激活cAMP反应元件结合蛋白，并抑制PASMC增殖。对MCT-PH大鼠进行静脉输注罂粟碱后，其肺动脉高压血流动力学参数异常及肺血管重构的程度可减轻40%~50%。本研究首次证实了PDE10A在进行性肺血管重构中的核心调控作用，研究结果为肺动脉高压的治疗提供了全新的潜在干预策略。