Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes.

Content Provider	CiteSeerX
Author	Kunichika, Naomi Judd W., L. Yu, Ying Kunichika, Hideki Thistlethwaite, Patricia A. Rubin, Lewis J. Yuan, Jason X. -J.
Abstract	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 Ca 2 � stimulates PASMC proliferation and the canonical transient receptor potential (TRPC) channels are an important pathway for Ca 2 � entry during PASMC proliferation. Bosentan (20–50 �M) significantly inhibited endothelin-1 – or platelet-derived growth factor (PDGF)–mediated PASMC growth and [ 3 H]thymidine uptake. In PASMCs, endothelin-1 (1 �M) 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.
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Subject Keyword	Pulmonary Vascular Myocytes Antiproliferative Effect Normal Pasmcs Trpc6 Expression Canonical Transient Receptor Potential Endothelin Receptor Blockade Whereas Bosentan Important Pathway Stimulates Pasmc Proliferation Pulmonary Artery Smooth Muscle Cell Trpc6 Channel Idiopathic Pulmonary Arterial Hypertension Thymidine Uptake Dual Endothelin Receptor Blocker Trpc6 Protein Level Upregulated Protein Expression Pasmc Proliferation Platelet-derived Growth Factor Pasmc Growth Cytoplasmic Ca
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