Journal
JOURNAL OF HYPERTENSION
Volume 33, Issue 5, Pages 981-992Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/HJH.0000000000000496
Keywords
endothelial dysfunction; fibrosis; inflammation; TGF-beta; TRPM4
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Funding
- FondoNacional de DesarrolloCientifico y Tecnologico - Fondecyt [1121078, 3140448, 1120240, 1120286, 1120380]
- Millennium Institute on Immunology and Immunotherapy [P09-016-F]
- Association-FrancaiseContre Les Myopathies AFM [16670]
- [UNAB-DI-281-13/R]
- [UNAB DI-209-12/N]
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Objective: To study whether transient receptor potential melastatin 4 (TRPM4) participates in endothelial fibrosis and to investigate the underlying mechanism. Methods: Primary human endothelial cells were used and pharmacological and short interfering RNA-based approaches were used to test the transforming growth factor beta (TGF-beta)/activin receptor-like kinase 5 (ALK5) pathway participation and contribution of TRPM7 ion channel. Results: Suppression of TRPM4 expression leads to decreased endothelial protein expression and increased expression of fibrotic and extracellular matrix markers. Furthermore, TRPM4 downregulation increases intracellular Ca2+ levels as a potential condition for fibrosis. The underlying mechanism of endothelial fibrosis shows that inhibition of TRPM4 expression induces TGF-beta 1 and TGF-beta 2 expression, which act through their receptor, ALK5, and the nuclear translocation of the profibrotic transcription factor smad4. Conclusion: TRPM4 acts to maintain endothelial features and its loss promotes fibrotic conversion via TGF-beta production. The regulation of TRPM4 levels could be a target for preserving endothelial function during inflammatory diseases.
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