Sildenafil Inhibits Human Pulmonary Artery Smooth Muscle Cell Proliferation by Decreasing Capacitative Ca2+ Entry

• Main Authors: Cong Wang, Jun Wang, Lan Zhao, Yuexiu Wang, Jie Liu, Luping Shi, Meng Xu, Chen Wang
• Format: Article
• Language: English
• Published: Elsevier 2008-01-01
• Series: Journal of Pharmacological Sciences
• Online Access: http://www.sciencedirect.com/science/article/pii/S1347861319313763

Ca2+ is a pivotal signal in human pulmonary artery smooth muscle cells (PASMCs) proliferation. Capacitative Ca2+ entry (CCE) via the store-operated channel (SOC), which encoded by the transient receptor potential (TRP) gene, is an important mechanism for regulating intracellular Ca2+ concentration ([Ca2+]i) in PASMCs. Sildenafil, a potent type 5 nucleotide-dependent phosphodiesterase (PDE) inhibitor, has been proposed as a therapeutic tool to treat or prevent pulmonary arterial hypertension (PAH); however, the mechanism of its antiproliferative effect on PASMCs remains unclear. This study was designed to investigate the possible antiproliferative mechanism of sildenafil on human PASMCs, namely, its effect on the Ca2+-signal pathway. Cultured normal PASMCs were treated with endothelin-1 (ET-1) or ET-1 plus sildenafil separately. Cell number and viability were determined with a hemocytometer or MTT assay. [Ca2+]i was measured by loading PASMCs with fura 2-AM. Expression of the TRPC1 gene and protein was detected by RT-PCR and Western blot, respectively. The results show that sildenafil dose-dependently inhibited the proliferation of PASMCs, the enhancement of basal [Ca2+]i level, increase of CCE, and upregulation of TRPC expression induced by ET-1. These results suggest that sildenafil potently inhibits ET-1–induced PASMCs proliferation and downregulation of CCE and TRPC expression may be responsible for its antiproliferative effect. Keywords:: store-operated channel, capacitative Ca2+ entry, transient receptor potential channel, pulmonary artery smooth muscle cell