Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata Nagakute, Aichi 480-1195, Japan; Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
Department of Pharmacy, College of Pharmacy, Kinjo Gakuin University, 2-1723 Omori Moriyamaku, Nagoya 463-8521, Japan.
Eur J Pharmacol. 2017 Sep 5;810:44-50. doi: 10.1016/j.ejphar.2017.06.010. Epub 2017 Jun 8.
Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease of the pulmonary artery resulting from a currently unidentified etiology. IPAH is pathologically characterized as sustained vasoconstriction and vascular remodeling of the pulmonary artery. Vascular remodeling is mediated by enhanced proliferation and reduced apoptosis in pulmonary arterial smooth muscle cells (PASMCs). Based on its pathological mechanism, specific phosphodiesterase type 5 (PDE5) inhibitors have been used in the treatment of IPAH. In addition to sildenafil, tadalafil has been approved for the treatment of IPAH. However, the effects of tadalafil on excessive proliferation of IPAH-PASMCs currently remain unknown. In the present study, the in vitro pharmacological profiles of tadalafil for cell proliferation and apoptosis were assessed in IPAH-PASMCs using MTT, BrdU incorporation, and caspase 3/7 assays. Expression analyses revealed that PDE5 mRNA and protein expression levels were markedly higher in IPAH-PASMCs than in normal-PASMCs. The treatment with tadalafil inhibited the excessive proliferation of IPAH-PASMCs in a concentration-dependent manner with an IC value of 4.5μM. On the other hand, tadalafil (0.03-100μM) did not affect cell growth of PASMCs from normal subjects and patients with chronic thromboembolic pulmonary hypertension (CTEPH). In addition, tadalafil induced apoptosis in IPAH-PASMCs. The antiproliferative and apoptotic effects of tadalafil were markedly stronger than those of sildenafil and vardenafil. The upregulated expression of PDE5 in IPAH-PASMCs was significantly attenuated by a long-term treatment with tadalafil. Taken together, these results indicate that tadalafil attenuates vascular remodeling by inhibiting cell proliferation, promoting apoptosis, and downregulating PDE5 in IPAH-PASMCs, thereby ameliorating IPAH.
特发性肺动脉高压（IPAH）是一种致命的肺动脉疾病，其病因目前尚不清楚。IPAH 的病理学特征为肺动脉持续收缩和血管重构。血管重构是由肺动脉平滑肌细胞（PASMCs）增殖增强和凋亡减少介导的。基于其病理机制，特定的磷酸二酯酶 5（PDE5）抑制剂已被用于 IPAH 的治疗。除了西地那非，他达拉非也已被批准用于 IPAH 的治疗。然而，他达拉非对 IPAH-PASMCs 过度增殖的影响目前尚不清楚。在本研究中，通过 MTT、BrdU 掺入和 caspase 3/7 测定，评估了他达拉非对 IPAH-PASMCs 细胞增殖和凋亡的体外药理学特性。表达分析显示，PDE5 mRNA 和蛋白表达水平在 IPAH-PASMCs 中明显高于正常-PASMCs。他达拉非以浓度依赖性方式抑制 IPAH-PASMCs 的过度增殖，IC 值为 4.5μM。另一方面，他达拉非（0.03-100μM）对来自正常受试者和慢性血栓栓塞性肺动脉高压（CTEPH）患者的 PASMCs 生长没有影响。此外，他达拉非诱导 IPAH-PASMCs 凋亡。他达拉非的抗增殖和促凋亡作用明显强于西地那非和伐地那非。他达拉非的长期治疗显著减弱了 IPAH-PASMCs 中 PDE5 的上调表达。综上所述，这些结果表明，他达拉非通过抑制细胞增殖、促进凋亡和下调 IPAH-PASMCs 中的 PDE5 来减轻血管重构，从而改善 IPAH。
