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

doi:10.1164/RCCM.200312-1668OC

Paper

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

Published Nov 15, 2004 · N. Kunichika, Judd W. Landsberg, Ying Yu

American journal of respiratory and critical care medicine

Q1 SJR score

100

Citations

5

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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 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.

In Vitro Study

Highly Cited

Study Snapshot

Bosentan's antiproliferative effect on pulmonary artery smooth muscle cells involves downregulating TRPC6 channels, potentially contributing to the overgrowth of smooth muscle cells in idiopathic pulmonary arterial hypertension patients.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

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

References

Hypoxia increases AP-1 binding activity by enhancing capacitative Ca2+ entry in human pulmonary artery endothelial cells.

Chronic hypoxia increases AP-1 binding activity in human pulmonary artery endothelial cells, potentially playing a role in pulmonary hypertension development by upregulating AP-1-responsive gene expression.

Cholesterol Depletion Impairs Vascular Reactivity to Endothelin-1 by Reducing Store-Operated Ca2+ Entry Dependent on TRPC1

Cholesterol influences vascular reactivity to endothelin-1 by affecting caveolar localization of TRPC1.

Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway

Pulmonary hypertension is induced by an Ang-1/TIE2/serotonin pathway, suggesting potential targets for treating this disease.

ET-1 activates Ca2+ sparks in PASMC: local Ca2+ signaling between inositol trisphosphate and ryanodine receptors.

Endothelin-1 activates calcium sparks in pulmonary arterial smooth muscle cells through the ETA receptor-PLC-IP3 pathway and local Ca2+ cross-signaling between IP3Rs and ryanodine receptors.

Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study.

Long-term treatment with bosentan is safe and maintains benefits on exercise capacity and hemodynamics in patients with pulmonary arterial hypertension.

Citations

Pathophysiology of Group 3 Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxia

Group 3 pulmonary hypertension is caused by hypoxic pulmonary vasoconstriction and pulmonary vascular remodeling, with potential new therapies targeting novel molecules to inhibit vascular remodeling.

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Impaired prostanoids, nitric oxide, and endothelin pathways play a role in cigarette smoke- and hypoxia-induced pulmonary vascular remodelling, suggesting potential therapeutic targets for COPD-associated pulmonary hypertension.

Deciphering the Mechanism of Wogonin, a Natural Flavonoid, on the Proliferation of Pulmonary Arterial Smooth Muscle Cells by Integrating Network Pharmacology and In Vitro Validation

Wogonin, a natural flavonoid, effectively inhibits pulmonary hypertension by regulating the HIF-1/NADPH oxidase 4 (NOX4) pathway and inhibiting PDGF-BB-mediated smooth muscle cell proliferation.

Mechanosensitivity in Pulmonary Circulation: Pathophysiological Relevance of Stretch-Activated Channels in Pulmonary Hypertension

Stretch-activated channels (SAC) play a crucial role in pulmonary arterial calcium homeostasis and could be potential novel drug targets for better management of pulmonary hypertension.

Pediatric Pulmonary Hypertension: Definitions, Mechanisms, Diagnosis, and Treatment.

Pediatric pulmonary hypertension (PPH) is a multifactorial disease with diverse etiologies and presenting features, and therapy focuses on pulmonary vasodilators and strategies to restore lung growth.