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BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice

Authors :
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
Annibale Alessandro Puca
Source :
Cell Death and Disease, Vol 14, Iss 8, Pp 1-11 (2023)
Publication Year :
2023
Publisher :
Nature Publishing Group, 2023.

Abstract

Abstract Long-living individuals (LLIs) escape age-related cardiovascular complications until the very last stage of life. Previous studies have shown that a Longevity-Associated Variant (LAV) of the BPI Fold Containing Family B Member 4 (BPIFB4) gene correlates with an extraordinarily prolonged life span. Moreover, delivery of the LAV-BPIFB4 gene exerted therapeutic action in murine models of atherosclerosis, limb ischemia, diabetic cardiomyopathy, and aging. We hypothesize that downregulation of BPIFB4 expression marks the severity of coronary artery disease (CAD) in human subjects, and supplementation of the LAV-BPIFB4 protects the heart from ischemia. In an elderly cohort with acute myocardial infarction (MI), patients with three-vessel CAD were characterized by lower levels of the natural logarithm (Ln) of peripheral blood BPIFB4 (p = 0.0077). The inverse association between Ln BPIFB4 and three-vessel CAD was confirmed by logistic regression adjusting for confounders (Odds Ratio = 0.81, p = 0.0054). Moreover, in infarcted mice, a single administration of LAV-BPIFB4 rescued cardiac function and vascularization. In vitro studies showed that LAV-BPIFB4 protein supplementation exerted chronotropic and inotropic actions on induced pluripotent stem cell (iPSC)-derived cardiomyocytes. In addition, LAV-BPIFB4 inhibited the pro-fibrotic phenotype in human cardiac fibroblasts. These findings provide a strong rationale and proof of concept evidence for treating CAD with the longevity BPIFB4 gene/protein.

Subjects

Subjects :
Cytology
QH573-671

Details

Language :
English
ISSN :
20414889
Volume :
14
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Cell Death and Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.348033df59064add9787c0ed75ff9450
Document Type :
article
Full Text :
https://doi.org/10.1038/s41419-023-06011-8