# BPIFB4

## Overview
The BPIFB4 gene encodes the protein BPI fold containing family B member 4, which is integral to various biological processes, particularly in vascular and endothelial health. This protein exists in multiple variants, including a longevity-associated variant (LAV) that has been studied for its role in enhancing vascular function through the modulation of endothelial nitric oxide synthase (eNOS). BPIFB4 is not only crucial for vascular health but also plays a significant role in the immune response and the regulation of endothelial and stem cell functions, which are vital for maintaining blood flow and vascular integrity. The gene and its protein products are implicated in several cellular mechanisms through interactions with other proteins such as 14-3-3 and Heat Shock Protein 90, which facilitate its function in promoting endothelial health and potentially influencing the progression of cardiovascular diseases (Spinelli2017LAV-BPIFB4; Villa2018A).

## Function
The BPIFB4 gene encodes the BPI fold containing family B member 4 protein, which plays a crucial role in various cellular and molecular processes essential for maintaining vascular and endothelial health. The longevity-associated variant (LAV) of BPIFB4 is particularly significant, enhancing the phosphorylation of endothelial nitric oxide synthase (eNOS), which is vital for vasodilation and proper vascular function. This process is mediated through increased binding to the 14-3-3 protein and interaction with Heat Shock Protein 90 (HSP90), facilitating eNOS activation and contributing to cardiovascular protection (Spinelli2017LAV-BPIFB4; Villa2018A).

In addition to its vascular roles, BPIFB4 is involved in the immune response. The protein influences the phenotype of macrophages and is implicated in modulating the immune-inflammatory response in vascular systems, which is crucial for managing endothelial functions and potentially influencing the progression of cardiovascular diseases (Dossena2020New; Puca2019Single).

Furthermore, BPIFB4 supports the homing and function of stem cells and endothelial precursor cells, essential for the repair and regeneration of aged and ischemic vessels. This supports not only vascular health but also contributes to the organismal outcomes of improved blood flow and reduced blood pressure in various models (Villa2018A).

## Clinical Significance
BPIFB4, particularly its longevity-associated variant (LAV-BPIFB4), has been linked to various cardiovascular diseases and conditions related to aging. Research indicates that alterations in the expression of BPIFB4 or mutations in the gene can significantly impact health. For instance, lower expression levels of BPIFB4 are associated with severe coronary artery disease (CAD), particularly in patients with three-vessel CAD, a critical and fatal form of the disease (Cattaneo2023BPIFB4). Additionally, the rare variant (RV-BPIFB4) has been associated with arterial hypertension and endothelial dysfunction, suggesting its potential as a biomarker for these conditions (Villa2018A).

Gene therapy using LAV-BPIFB4 has shown promise in various cardiovascular conditions by demonstrating anti-atherosclerotic, anti-hypertensive, pro-angiogenic, and neuroprotective activities in cardiovascular animal models (Cattaneo2023BPIFB4). Furthermore, the expression of BPIFB4, particularly its LAV, has been linked to improved aging and reduced risk of age-related cardiovascular diseases, indicating its role in healthy aging and possibly in the prevention of age-related vascular diseases (Villa2018A). Conversely, the RV-BPIFB4 variant impairs nitric oxide signaling, negatively affecting vascular function and blood pressure, which could contribute to cardiovascular diseases (Vecchione2017A).

## Interactions
BPIFB4, specifically its longevity-associated variant (LAV-BPIFB4), interacts with several proteins that are crucial for its function in cellular processes. Notably, BPIFB4 forms complexes with nucleolin (NCL) and 14-3-3 proteins. The interaction with NCL is essential for the pro-angiogenic action of LAV-BPIFB4 in aged IHF-PCs, as demonstrated by the inhibition of this action when NCL is silenced (Cattaneo2023The). Additionally, LAV-BPIFB4 shows a distinct interaction with 14-3-3 proteins, which is more efficient compared to the wild-type BPIFB4. This interaction is supported by co-immunoprecipitation experiments showing detectable complexes of BPIFB4-14-3-3 when cells are transfected with LAV-BPIFB4 (Villa2015Genetic).

BPIFB4 also interacts with protein kinase RNA-like endoplasmic reticulum kinase (PERK), enhancing the phosphorylation of eukaryotic translation initiation factor 2-alpha and reducing endoplasmic reticulum stress (Villa2015Genetic). Furthermore, the phosphorylation of BPIFB4 by PERK at serine 75 is crucial for its interaction with 14-3-3 proteins and the subsequent recruitment of heat shock protein 90 (HSP90), which is necessary for activating endothelial nitric oxide synthase (eNOS) (Villa2015Genetic; Villa2018A). These interactions underline the role of BPIFB4 in modulating endothelial function and vascular health.


## References


[1. (Dossena2020New) Marta Dossena, Anna Ferrario, Valentina Lopardo, Elena Ciaglia, and Annibale Alessandro Puca. New insights for bpifb4 in cardiovascular therapy. International Journal of Molecular Sciences, 21(19):7163, September 2020. URL: http://dx.doi.org/10.3390/ijms21197163, doi:10.3390/ijms21197163. (11 citations) 10.3390/ijms21197163](https://doi.org/10.3390/ijms21197163)

[2. (Vecchione2017A) Carmine Vecchione, Francesco Villa, Albino Carrizzo, Chiara Carmela Spinelli, Antonio Damato, Mariateresa Ambrosio, Anna Ferrario, Michele Madonna, Annachiara Uccellatore, Silvia Lupini, Anna Maciag, Larisa Ryskalin, Luciano Milanesi, Giacomo Frati, Sebastiano Sciarretta, Riccardo Bellazzi, Stefano Genovese, Antonio Ceriello, Alberto Auricchio, Alberto Malovini, and Annibale Alessandro Puca. A rare genetic variant of bpifb4 predisposes to high blood pressure via impairment of nitric oxide signaling. Scientific Reports, August 2017. URL: http://dx.doi.org/10.1038/s41598-017-10341-x, doi:10.1038/s41598-017-10341-x. (20 citations) 10.1038/s41598-017-10341-x](https://doi.org/10.1038/s41598-017-10341-x)

[3. (Puca2019Single) Annibale Alessandro Puca, Albino Carrizzo, Chiara Spinelli, Antonio Damato, Mariateresa Ambrosio, Francesco Villa, Anna Ferrario, Anna Maciag, Francesco Fornai, Paola Lenzi, Valentina Valenti, Flavio di Nonno, Giulio Accarino, Michele Madonna, Maurizio Forte, Gaetano Calì, Andrea Baragetti, Giuseppe Danilo Norata, Alberico Luigi Catapano, Monica Cattaneo, Raffaele Izzo, Valentina Trimarco, Francesco Montella, Francesco Versaci, Alberto Auricchio, Giacomo Frati, Sebastiano Sciarretta, Paolo Madeddu, Elena Ciaglia, and Carmine Vecchione. Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in apoe knockout mice through a cxcr4-mediated mechanism. European Heart Journal, 41(26):2487–2497, July 2019. URL: http://dx.doi.org/10.1093/eurheartj/ehz459, doi:10.1093/eurheartj/ehz459. (63 citations) 10.1093/eurheartj/ehz459](https://doi.org/10.1093/eurheartj/ehz459)

[4. (Cattaneo2023BPIFB4) Monica Cattaneo, Aneta Aleksova, Alberto Malovini, Elisa Avolio, Anita Thomas, Valeria Vincenza Alvino, Michael Kilcooley, Marie Pieronne-Deperrois, Antoine Ouvrard-Pascaud, Anna Maciag, Gaia Spinetti, Sophie Kussauer, Heiko Lemcke, Anna Skorska, Praveen Vasudevan, Stefania Castiglione, Angela Raucci, Robert David, Vincent Richard, Antonio Paolo Beltrami, Paolo Madeddu, and Annibale Alessandro Puca. Bpifb4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice. Cell Death & Disease, August 2023. URL: http://dx.doi.org/10.1038/s41419-023-06011-8, doi:10.1038/s41419-023-06011-8. (1 citations) 10.1038/s41419-023-06011-8](https://doi.org/10.1038/s41419-023-06011-8)

[5. (Villa2018A) Francesco Villa, Albino Carrizzo, Anna Ferrario, Anna Maciag, Monica Cattaneo, Chiara Spinelli, Francesco Montella, Antonio Damato, Elena Ciaglia, and Annibale Puca. A model of evolutionary selection: the cardiovascular protective function of the longevity associated variant of bpifb4. International Journal of Molecular Sciences, 19(10):3229, October 2018. URL: http://dx.doi.org/10.3390/ijms19103229, doi:10.3390/ijms19103229. (18 citations) 10.3390/ijms19103229](https://doi.org/10.3390/ijms19103229)

[6. (Cattaneo2023The) Monica Cattaneo, Antonio P Beltrami, Anita C Thomas, Gaia Spinetti, Valeria Vincenza Alvino, Elisa Avolio, Claudia Veneziano, Irene Giulia Rolle, Sandro Sponga, Elena Sangalli, Anna Maciag, Fabrizio Dal Piaz, Carmine Vecchione, Aishah Alenezi, Stephen Paisey, Annibale A Puca, and Paolo Madeddu. The longevity-associated bpifb4 gene supports cardiac function and vascularization in ageing cardiomyopathy. Cardiovascular Research, 119(7):1583–1595, January 2023. URL: http://dx.doi.org/10.1093/cvr/cvad008, doi:10.1093/cvr/cvad008. (9 citations) 10.1093/cvr/cvad008](https://doi.org/10.1093/cvr/cvad008)

[7. (Spinelli2017LAV-BPIFB4) Chiara Carmela Spinelli, Albino Carrizzo, Anna Ferrario, Francesco Villa, Antonio Damato, Mariateresa Ambrosio, Michele Madonna, Giacomo Frati, Sergio Fucile, Miriam Sciaccaluga, Mario Capunzo, Gaetano Calì, Luciano Milanesi, Anna Maciag, Annibale Alessandro Puca, and Carmine Vecchione. Lav-bpifb4 isoform modulates enos signalling through ca2+/pkc-alpha-dependent mechanism. Cardiovascular Research, 113(7):795–804, April 2017. URL: http://dx.doi.org/10.1093/cvr/cvx072, doi:10.1093/cvr/cvx072. (27 citations) 10.1093/cvr/cvx072](https://doi.org/10.1093/cvr/cvx072)

[8. (Villa2015Genetic) Francesco Villa, Albino Carrizzo, Chiara C. 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 Calì, Stefan Schreiber, Thomas Perls, Sergio Fucile, Francesca Mulas, Almut Nebel, Riccardo Bellazzi, Paolo Madeddu, Carmine Vecchione, and Annibale A. Puca. Genetic analysis reveals a longevity-associated protein modulating endothelial function and angiogenesis. Circulation Research, 117(4):333–345, July 2015. URL: http://dx.doi.org/10.1161/CIRCRESAHA.117.305875, doi:10.1161/circresaha.117.305875. (89 citations) 10.1161/CIRCRESAHA.117.305875](https://doi.org/10.1161/CIRCRESAHA.117.305875)