TY - JOUR
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 - 2017/8/29
Y1 - 2017/8/29
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.
KW - Journal Article
U2 - 10.1038/s41598-017-10341-x
DO - 10.1038/s41598-017-10341-x
M3 - Article
C2 - 28852218
VL - 7
SP - 9706
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
ER -