The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy

• Published in: Cardiovascular research Vol. 119; no. 7; pp. 1583 - 1595
• Main Authors: Cattaneo, Monica, Beltrami, Antonio P, Thomas, Anita C, Spinetti, Gaia, Alvino, Valeria Vincenza, Avolio, Elisa, Veneziano, Claudia, Rolle, Irene Giulia, Sponga, Sandro, Sangalli, Elena, Maciag, Anna, Dal Piaz, Fabrizio, Vecchione, Carmine, Alenezi, Aishah, Paisey, Stephen, Puca, Annibale A, Madeddu, Paolo
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 04.07.2023
• Subjects: Aging - genetics; Animals; Cardiomyopathies - genetics; Cardiomyopathies - pathology; Cardiovascular Physiological Phenomena; Genotype; Longevity - genetics; Mice; Original; Pericytes - pathology; Angiogenesis; Myocardial fibrosis; Perivascular cells; Nucleolin; Ageing
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvad008

Abstract Aims The ageing heart naturally incurs a progressive decline in function and perfusion that available treatments cannot halt. However, some exceptional individuals maintain good health until the very late stage of their life due to favourable gene–environment interaction. We have previously shown that carriers of a longevity-associated variant (LAV) of the BPIFB4 gene enjoy prolonged health spans and lesser cardiovascular complications. Moreover, supplementation of LAV-BPIFB4 via an adeno-associated viral vector improves cardiovascular performance in limb ischaemia, atherosclerosis, and diabetes models. Here, we asked whether the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart’s spontaneous ageing. Methods and results Immunohistological studies showed a remarkable reduction in vessel coverage by pericytes in failing hearts explanted from elderly patients. This defect was attenuated in patients carrying the homozygous LAV-BPIFB4 genotype. Moreover, pericytes isolated from older hearts showed low levels of BPIFB4, depressed pro-angiogenic activity, and loss of ribosome biogenesis. LAV-BPIFB4 supplementation restored pericyte function and pericyte-endothelial cell interactions through a mechanism involving the nucleolar protein nucleolin. Conversely, BPIFB4 silencing in normal pericytes mimed the heart failure pericytes. Finally, gene therapy with LAV-BPIFB4 prevented cardiac deterioration in middle-aged mice and rescued cardiac function and myocardial perfusion in older mice by improving microvasculature density and pericyte coverage. Conclusions We report the success of the LAV-BPIFB4 gene/protein in improving homeostatic processes in the heart’s ageing. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people. Graphical Abstract Graphical Abstract Schematic diagram summarizes dysfunctional key mechanisms and phenotypical features of cardiac ageing that are rescued by LAV-BPIFB4. Cardiac ageing is characterized by abnormal ribosomal biogenesis, DNA damage and senescence, and imbalance of inflammation and angiogenesis (red symbols and arrows). Left panel: Dysfunctional mechanisms rescued by LAV-BPIFB4 (green arrows). (i) Ribosomal biogenesis: LAV-BPIFB4 promotes rRNA transcription and ribosomal biogenesis. (ii) Senescence: LAV-BPIFB4 reduces the frequency of the Ki67neg and gH2AXpos antigenic phenotype and senescence markers SAβG, p16lnk4A and H3. (iii) Angiogenesis: LAV-BPIFB4 synergically works with NCL to induce vascular cell network formation. Right panel: LAV-BPIFB4 in carriers and effects of LAV-BPIFB4 supplementation to senescent vascular cells and aged mice. The LAV-BPIFB4 genotype is associated with partially preserved pericyte coverage. LAV-BPIFB4 supplementation rescues human pericytes in vitro and improves myocardial vascular density and cardiac function in aged mice.