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, Jason X.J. Yuan

Research output: Contribution to journalArticle

73 Scopus citations

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 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 endotherm 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.

Original languageEnglish (US)
Pages (from-to)1101-1107
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume170
Issue number10
DOIs
StatePublished - Nov 15 2004
Externally publishedYes

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Keywords

  • Ca channels
  • Endothelin-1
  • Transient receptor potential cation channel

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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