A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling

Carmine Vecchione, Francesco Villa, Albino Carrizzo, Chiara Carmela Spinelli, Antonio Damato, Mariateresa Ambrosio, Anna Ferrario, Michele Madonna, Annachiara Uccellatore, Silvia Lupini, Anna Maciag, Larisa Ryskalin, Luciano Milanesi, Giacomo Frati, Sebastiano Sciarretta, Riccardo Bellazzi, Stefano Genovese, Antonio Ceriello, Alberto Auricchio, Alberto MaloviniAnnibale Alessandro Puca

Research output: Contribution to journalArticle

Abstract

BPIFB4 is associated with exceptional longevity: four single-nucleotide polymorphisms distinguish the wild-type form from a longevity-associated variant conferring positive effects on blood pressure. The effect of a rare variant (RV; allele frequency, 4%) on blood pressure is unknown. Here, we show that overexpression of RV-BPIFB4 in ex-vivo mouse vessels impairs phosphorylation of endothelial nitric oxide synthase (eNOS), blunting acetylcholine-evoked vasorelaxation; in vivo, virally mediated overexpression of RV-BPIFB4 increases blood pressure, an action absent in eNOS-deficient mice. In humans, we found RV carriers to have increased diastolic blood pressure, a finding that was more marked in subjects on anti-hypertensive medication; moreover, recombinant RV-BPIFB4 protein impaired eNOS function in ex-vivo human vessels. Thus, RV-BPIFB4 acts directly on blood pressure homeostasis and may represent a novel biomarker of vascular dysfunction and hypertension.

Original languageEnglish
Pages (from-to)9706
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Aug 29 2017

Keywords

  • Journal Article

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