LAV-BPIFB4 isoform modulates eNOS signalling through Ca2+/PKC-alpha-dependent mechanism

Chiara Carmela Spinelli, Albino Carrizzo, Anna Ferrario, Francesco Villa, Antonio Damato, Mariateresa Ambrosio, Michele Madonna, Giacomo Frati, Sergio Fucile, Miriam Sciaccaluga, Mario Capunzo, Gaetano Calì, Luciano Milanesi, Anna Maciag, Annibale Alessandro Puca, Carmine Vecchione

Research output: Contribution to journalArticlepeer-review

Abstract

Aims: Ageing is associated with impairment of endothelial nitric oxide synthase (eNOS) and progressive reduction in endothelial function. A genetic study on long-living individuals—who are characterized by delays in ageing and in the onset of cardiovascular disease—previously revealed I229V (rs2070325) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) as a longevity-associated variant (LAV); the LAV protein enhanced endothelial NO production and vasorelaxation through a protein kinase R–like endoplasmic reticulum kinase/14-3-3/heat shock protein 90 signal. Here, we further characterize the molecular mechanisms underlying LAV-BPIFB4-dependent enhancement of vascular function. Methods and results: LAV-BPIFB4 upregulated eNOS function via mobilization of Ca2+ and activation of protein kinase C alpha (PKCα). Indeed, the overexpression of LAV-BPIFB4 in human endothelial cells enhanced ATP-induced Ca2+ mobilization and the translocation of PKCa to the plasma membrane. Coherently, pharmacological inhibition of PKCα blunted the positive effect of LAV-BPIFB4 on eNOS and endothelial function. In addition, although LAV-BPIFB4 lost the ability to activate PKCα and eNOS in ex vivo vessels studied in an external Ca2+-free medium and in vessels from eNOS-/- mice, it still potentiated endothelial activity, recruiting an alternative mechanism dependent upon endothelium-derived hyperpolarizing factor (EDHF). Conclusions: We have identified novel molecular determinants of the beneficial effects of LAV-BPIFB4 on endothelial function, showing the roles of Ca2+ mobilization and PKCα in eNOS activation and of EDHF when eNOS is inhibited. These results highlight the role LAV-BPIFB4 can have in restoring signals that are lost during ageing.

Original languageEnglish
Pages (from-to)795-804
Number of pages10
JournalCardiovascular Research
Volume113
Issue number7
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • BPIFB4
  • Endothelium
  • Nitric oxide
  • PKCα
  • Vascular function

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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