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

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 ORCID: https://orcid.org/0000-0002-2274-3708, Puca, Annibale A. and Madeddu, Paolo 2023. The longevity-associated BPIFB4 gene supports cardiac function and vascularization in ageing cardiomyopathy. Cardiovascular Research 119 (7) , pp. 1583-1595. 10.1093/cvr/cvad008

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Oxford University Press
ISSN:	0008-6363
Date of First Compliant Deposit:	15 August 2023
Date of Acceptance:	11 January 2023
Last Modified:	15 Aug 2023 16:21
URI:	https://orca.cardiff.ac.uk/id/eprint/158563

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