Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis

作者：Francesco Villa, Albino Carrizzo, Chiara Spinelli, Anna Ferrario, Alberto Malovini, Anna Maciąg, Antonio Damato, Alberto Auricchio, Gaia Spinetti, Elena Sangalli, Zexu Dang, Michele Madonna, Mariateresa Ambrosio, Leopoldo Sitia, Paolo Bigini, Gaetano Calı̀, Stefan Schreiber, Thomas T. Perls, Sergio Fucile, Francesca Mulas, Almut Nebel, Riccardo Bellazzi, Paolo Madeddu, Carmine Vecchione, Annibale Alessandro Puca · 发表于：Circulation Research · 年份：2015 · DOI：10.1161/circresaha.117.305875 · 被引用次数：92 · 研究领域：14-3-3 protein interactions、Angiogenesis and VEGF in Cancer、Genetics, Aging, and Longevity in Model Organisms

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...