Abstract
Aims
The aging 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 ischemia, atherosclerosis, and diabetes models. Here, we asked if the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart’s spontaneous aging.
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 aging. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.
The aging 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 ischemia, atherosclerosis, and diabetes models. Here, we asked if the LAV-BPIFB4 gene could address the unmet therapeutic need to delay the heart’s spontaneous aging.
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 aging. These findings open to using LAV-BPIFB4 to reverse the decline of heart performance in older people.
| Original language | English |
|---|---|
| Article number | cvad008 |
| Pages (from-to) | 1583-1595 |
| Number of pages | 13 |
| Journal | Cardiovascular Research |
| Volume | 119 |
| Issue number | 7 |
| Early online date | 13 Jan 2023 |
| DOIs | |
| Publication status | E-pub ahead of print - 13 Jan 2023 |
Bibliographical note
Funding Information:Cartoons representing cells and synopsis pictures were created by BioRender.com. and Servier Medical Art (http://www.servier.com). This work was supported by grants from (i) the British Heart Foundation (PG/18/66/33838, Transferring healthy longevity gene to improve age-related heart dysfunction) to P.M. and A.A.P, (ii) the Italian Ministry of Health, Ricerca Corrente to the IRCCS MultiMedica and Ministry of Health (RF-2016-02364864) to A.A.P. and C.V., (iii) Regione Friuli Venezia Giulia, within the framework of ‘Legge Regionale 17/2004: Contributi per la Ricerca clinica, traslazionale, di base, epidemiologica e organizzativa’; Project HEARTzheimer’ to A.P.B.
Funding Information:
This work was supported by grants from (i) the British Heart Foundation (PG/18/66/33838, Transferring healthy longevity gene to improve age-related heart dysfunction) to P.M. and A.A.P, (ii) the Italian Ministry of Health, Ricerca Corrente to the IRCCS MultiMedica and Ministry of Health (RF-2016-02364864) to A.A.P. and C.V., (iii) Regione Friuli Venezia Giulia, within the framework of ‘Legge Regionale 17/2004: Contributi per la Ricerca clinica, traslazionale, di base, epidemiologica e organizzativa’; Project HEARTzheimer’ to A.P.B.
Publisher Copyright:
© The Author(s) 2023.