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

• Published in: Cell death & disease Vol. 14; no. 8; p. 523
• Main Authors: Cattaneo, Monica, Aleksova, Aneta, Malovini, Alberto, Avolio, Elisa, Thomas, Anita, Alvino, Valeria Vincenza, Kilcooley, Michael, Pieronne-Deperrois, Marie, Ouvrard-Pascaud, Antoine, Maciag, Anna, Spinetti, Gaia, Kussauer, Sophie, Lemcke, Heiko, Skorska, Anna, Vasudevan, Praveen, Castiglione, Stefania, Raucci, Angela, David, Robert, Richard, Vincent, Beltrami, Antonio Paolo, Madeddu, Paolo, Puca, Annibale Alessandro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-08-2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/51; 14; 14/63; 42; 42/44; 631/154/152; 64; 64/60; 692/699/75/2/1674; Animal models; Antibodies; Arteriosclerosis; Biochemistry; Biomedical and Life Sciences; Cardiomyocytes; Cardiomyopathy; Cardiovascular disease; Cell Biology; Cell Culture; Coronary artery disease; Diabetes mellitus; Fibroblasts; Geriatrics; Haplotypes; Heart; Heart diseases; Immunology; Ischemia; Life Sciences; Life span; Longevity; Myocardial infarction; Peripheral blood; Phenotypes; Pluripotency; Vascularization
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06011-8

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.