Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death

Alvaro Becerra, Cesar Echeverra, Diego Varela, Daniela Sarmiento, Ricardo Armisn, Felipe Nuez-Villena, Mario Montecinos, Felipe Simon

Resultado de la investigación: Contribución a una revistaArtículo

54 Citas (Scopus)

Resumen

Aims Endothelial dysfunction is decisive in the progression of cardiovascular diseases. Lipopolysaccharide (LPS)-induced reactive oxygen species (ROS)-mediated endothelial cell death is a main feature observed in inflammation secondary to endotoxaemia, emerging as a leading cause of death among critically ill patients in intensive care units. However, the molecular mechanism underlying LPS-induced endothelial cell death is not well understood. Transient receptor protein melastatin 4 (TRPM4) is an ion channel associated with cell death that is expressed in endothelium and modulated by ROS. Here, we investigate the role of TRPM4 in LPS-induced endothelial cell death, testing whether suppression of the expression of TRPM4 confers endothelial cell resistance to LPS challenge. Methods and resultsUsing primary cultures of human umbilical vein endothelial cells (HUVEC), we demonstrate that TRPM4 is critically involved in LPS-induced endothelial cell death. HUVEC exposed to LPS results in Na-dependent cell death. Pharmacological inhibition of TRPM4 with 9-phenanthrol or glibenclamide protects endothelium against LPS exposure for 48 h. Furthermore, TRPM4-like currents increase in cells pre-treated with LPS and inhibited with glibenclamide. Of note, suppression of TRPM4 expression by siRNA or suppression of its activity in a dominant negative mutant is effective in decreasing LPS-induced endothelial cell death when cells are exposed to LPS for 2430 h. ConclusionTRPM4 is critically involved in LPS-induced endothelial cell death. These results demonstrate that either pharmacological inhibition of TRPM4, suppression of TRPM4 expression, or inhibition of TRPM4 activity are able to protect endothelium against LPS injury. These results are useful in sepsis drug design and development of new strategies for sepsis therapy.

Idioma originalInglés
Páginas (desde-hasta)677-684
Número de páginas8
PublicaciónCardiovascular Research
Volumen91
N.º4
DOI
EstadoPublicada - 1 sep 2011

Áreas temáticas de ASJC Scopus

  • Cardiología y medicina cardiovascular
  • Fisiología (médica)
  • Fisiología

Huella Profundice en los temas de investigación de 'Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death'. En conjunto forman una huella única.

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    Becerra, A., Echeverra, C., Varela, D., Sarmiento, D., Armisn, R., Nuez-Villena, F., Montecinos, M., & Simon, F. (2011). Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death. Cardiovascular Research, 91(4), 677-684. https://doi.org/10.1093/cvr/cvr135