Bosentan inhibits transient receptor potential channel expression in pulmonary vascular myocytes
| Autor: | Hideki Kunichika, Ying Yu, Judd W. Landsberg, Patricia A. Thistlethwaite, Naomi Kunichika, Lewis J. Rubin, Jason X.-J. Yuan |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Pulmonary and Respiratory Medicine
Male medicine.medical_specialty medicine.medical_treatment Hypertension Pulmonary Blotting Western Myocytes Smooth Muscle Pulmonary Artery Critical Care and Intensive Care Medicine Sensitivity and Specificity Sampling Studies TRPC6 Rats Sprague-Dawley Reference Values Internal medicine Intensive care medicine Animals TRPC Cells Cultured Cell Proliferation Sulfonamides biology Endothelin-1 business.industry Receptors Endothelin Growth factor Bosentan Calcium Channel Blockers Endothelin 1 Rats Up-Regulation Endocrinology biology.protein Calcium Channels Endothelium Vascular business Endothelin receptor Platelet-derived growth factor receptor medicine.drug |
| Zdroj: | American journal of respiratory and critical care medicine. 170(10) |
| ISSN: | 1073-449X |
| Popis: | 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 microM) significantly inhibited endothelin-1- or platelet-derived growth factor (PDGF)-mediated PASMC growth and [3H]thymidine uptake. In PASMCs, endothelin-1 (1 microM) 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. |
| Databáze: | OpenAIRE |
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