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

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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
Article number9706
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

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Nitric Oxide
Blood Pressure
Hypertension
Nitric Oxide Synthase Type III
Gene Frequency
Vasodilation
Antihypertensive Agents
Acetylcholine
Single Nucleotide Polymorphism
Blood Vessels
Homeostasis
Biomarkers
Phosphorylation
Proteins

ASJC Scopus subject areas

  • General

Cite this

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title = "A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling",
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.",
author = "Carmine Vecchione and Francesco Villa and Albino Carrizzo and Spinelli, {Chiara Carmela} and Antonio Damato and Mariateresa Ambrosio and Anna Ferrario and Michele Madonna and Annachiara Uccellatore and Silvia Lupini and Anna Maciag and Larisa Ryskalin and Luciano Milanesi and Giacomo Frati and Sebastiano Sciarretta and Riccardo Bellazzi and Stefano Genovese and Antonio Ceriello and Alberto Auricchio and Alberto Malovini and Puca, {Annibale Alessandro}",
year = "2017",
month = "12",
day = "1",
doi = "10.1038/s41598-017-10341-x",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
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T1 - A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling

AU - Vecchione, Carmine

AU - Villa, Francesco

AU - Carrizzo, Albino

AU - Spinelli, Chiara Carmela

AU - Damato, Antonio

AU - Ambrosio, Mariateresa

AU - Ferrario, Anna

AU - Madonna, Michele

AU - Uccellatore, Annachiara

AU - Lupini, Silvia

AU - Maciag, Anna

AU - Ryskalin, Larisa

AU - Milanesi, Luciano

AU - Frati, Giacomo

AU - Sciarretta, Sebastiano

AU - Bellazzi, Riccardo

AU - Genovese, Stefano

AU - Ceriello, Antonio

AU - Auricchio, Alberto

AU - Malovini, Alberto

AU - Puca, Annibale Alessandro

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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.

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