TY - JOUR
T1 - BPIFB4 and its longevity-associated haplotype protect from cardiac ischemia in humans and mice
AU - Cattaneo, Monica
AU - Aleksova, Aneta
AU - Malovini, Alberto
AU - Avolio, Elisa
AU - Thomas, Anita
AU - Alvino, Valeria Vincenza
AU - Kilcooley, Michael
AU - Pieronne-Deperrois, Marie
AU - Ouvrard-Pascaud, Antoine
AU - Maciag, Anna
AU - Spinetti, Gaia
AU - Kussauer, Sophie
AU - Lemcke, Heiko
AU - Skorska, Anna
AU - Vasudevan, Praveen
AU - Castiglione, Stefania
AU - Raucci, Angela
AU - David, Robert
AU - Richard, Vincent
AU - Beltrami, Antonio Paolo
AU - Madeddu, Paolo
AU - Puca, Annibale Alessandro
N1 - Publisher Copyright:
© The Author(s) 2023.
PY - 2023/8/15
Y1 - 2023/8/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85168061857
U2 - 10.1038/s41419-023-06011-8
DO - 10.1038/s41419-023-06011-8
M3 - Article (Academic Journal)
C2 - 37582912
AN - SCOPUS:85168061857
SN - 2041-4889
VL - 14
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 8
M1 - 523
ER -
