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

Journal of Pharmacological Sciences

Jun Wang¹  Cong Wang³  Jie Liu¹  Yuexiu Wang³  Luping Shi¹  Meng Xu¹  Lan Zhao²  Chen Wang³ 

[1] Department of Physiology, Capital Medical University, China;Section on Clinical Pharmacology, Faculty of Medicine, Imperial College, Hammersmith Hospital, United Kingdom;Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, China

关键词: store-operated channel;    capacitative Ca2+ entry;    transient receptor potential channel;    pulmonary artery smooth muscle cell;   

DOI  :  10.1254/jphs.08069FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(28)Cited-By(13)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.

【 授权许可】

Unknown