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2015 ; 117
(4
): 333-45
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Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial
Function and Angiogenesis
#MMPMID26034043
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; Carrizzo A
; Spinelli CC
; Ferrario A
; Malovini A
; Maci?g A
; Damato A
; Auricchio A
; Spinetti G
; Sangalli E
; Dang Z
; Madonna M
; Ambrosio M
; Sitia L
; Bigini P
; Calì G
; Schreiber S
; Perls T
; Fucile S
; Mulas F
; Nebel A
; Bellazzi R
; Madeddu P
; Vecchione C
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Circ Res
2015[Jul]; 117
(4
): 333-45
PMID26034043
show ga
RATIONALE: Long living individuals show delay of aging, which is characterized by
the progressive loss of cardiovascular homeostasis, along with reduced
endothelial nitric oxide synthase activity, endothelial dysfunction, and
impairment of tissue repair after ischemic injury. OBJECTIVE: Exploit genetic
analysis of long living individuals to reveal master molecular regulators of
physiological aging and new targets for treatment of cardiovascular disease.
METHODS AND RESULTS: We show that the polymorphic variant rs2070325 (Ile229Val)
in bactericidal/permeability-increasing fold-containing-family-B-member-4
(BPIFB4) associates with exceptional longevity, under a recessive genetic model,
in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental
to maintenance of cellular and vascular homeostasis through regulation of protein
synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic
reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90,
which is facilitated by the longevity-associated variant. In isolated vessels,
BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits
endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene
transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide
synthase signaling, rescues endothelial dysfunction, and reduces blood pressure
levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is
abundantly expressed in circulating CD34(+) cells of long living individuals, and
its knock-down in endothelial progenitor cells precludes their capacity to
migrate toward the chemoattractant SDF-1. In a murine model of peripheral
ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes
the recruitment of hematopoietic stem cells, reparative vascularization, and
reperfusion of the ischemic muscle. CONCLUSIONS: Longevity-associated
variant-BPIFB4 may represent a novel therapeutic tool to fight endothelial
dysfunction and promote vascular reparative processes.
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