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EnglishBPIFB4 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.
| Autori interni: | |
| Autori: | Vecchione, C; Villa, F; Carrizzo, A; Spinelli, Cc; Damato, A; Ambrosio, M; Ferrario, A; Madonna, M; Uccellatore, A; Lupini, S; Maciag, A; Ryskalin, Larisa; Milanesi, L; Frati, G; Sciarretta, S; Bellazzi, R; Genovese, S; Ceriello, A; Auricchio, A; Malovini, A; Puca, A. A. |
| Titolo: | A rare genetic variant of BPIFB4 predisposes to high blood pressure via impairment of nitric oxide signaling. |
| Anno del prodotto: | 2017 |
| 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. |
| Digital Object Identifier (DOI): | 10.1038/s41598-017-10341-x |
| Appare nelle tipologie: | 1.1 Articolo in rivista |
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