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Published ahead of print on August 18, 2004, doi:10.1164/rccm.200312-1668OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1101-1107, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200312-1668OC

Original Article

Bosentan Inhibits Transient Receptor Potential Channel Expression in Pulmonary Vascular Myocytes

Naomi Kunichika, Judd W. Landsberg, Ying Yu, Hideki Kunichika, Patricia A. Thistlethwaite, Lewis J. Rubin and Jason X.-J. Yuan

Department of Medicine and Department of Surgery, University of California, San Diego, La Jolla, California

Correspondence and requests for reprints should be addressed to Jason X.-J. Yuan, M.D., Ph.D., Division of Pulmonary and Critical Care Medicine, University of California, San Diego, Medical Teaching Facility, Room 252, 9500 Gilman Drive, La Jolla, CA 92093-0725. E-mail: xiyuan{at}ucsd.edu

Bosentan, a dual endothelin receptor blocker, has been used clinically to treat idiopathic pulmonary arterial hypertension (IPAH). However, the mechanism of its antiproliferative effect on pulmonary artery smooth muscle cells (PASMCs) remains unclear. A rise in cytoplasmic Ca2+ stimulates PASMC proliferation and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca2+ entry during PASMC proliferation. Bosentan (20–50 µM) significantly inhibited endothelin-1– or platelet-derived growth factor (PDGF)–mediated PASMC growth and [3H]thymidine uptake. In PASMCs, endothelin-1 (1 µM) and PDGF (10 ng/ml) both upregulated protein expression of TRPC6, whereas bosentan markedly downregulated TRPC6 protein levels. Furthermore, TRPC6 expression in PASMCs from patients with IPAH was greater than in normal PASMCs, and the antiproliferative effect of bosentan was significantly enhanced in IPAH-PASMCs in comparison with normal PASMCs. These observations demonstrate that the antiproliferative effect of bosentan on PASMCs involves the downregulation of TRPC6 channels via a mechanism possibly independent of endothelin receptor blockade. The greater effect of bosentan on IPAH-PASMCs than on normal PASMCs suggests that increased TRPC6 expression and function may be involved in the overgrowth of PASMCs in patients with IPAH.

Key Words: Ca2+ channels • endothelin-1 • transient receptor potential cation channel




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