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Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF ‐1/ CXCR4 signalling pathway
Author(s) -
Dang Zexu,
Avolio Elisa,
Thomas Anita C.,
Faulkner Ashton,
Beltrami Antonio P.,
Cervellin Celeste,
Carrizzo Albino,
Maciag Anna,
Gu Yue,
Ciaglia Elena,
Finato Nicoletta,
Damato Antonio,
Spinetti Gaia,
Alenzi Aishah,
Paisey Stephen J.,
Vecchione Carmine,
Puca Annibale A.,
Madeddu Paolo
Publication year - 2020
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1002/ejhf.1840
Subject(s) - medicine , diabetic cardiomyopathy , cardiac function curve , endocrinology , longevity , diabetes mellitus , heart failure , cardiomyopathy , gerontology
Abstract Aims Homozygosity for a four‐missense single‐nucleotide polymorphism haplotype of the human BPIFB4 gene is enriched in long‐living individuals. Delivery of this longevity‐associated variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell‐derived factor‐1 (SDF‐1). Here, we investigated if delivery of the LAV‐BPIFB4 gene may attenuate the progression of diabetic cardiomyopathy. Methods and results Compared with age‐matched lean controls, diabetic db/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV‐BPIFB4 gene therapy using an adeno‐associated viral vector serotype 9 (AAV9) . In contrast, AAV9 wild‐type‐ BPIFB4 exerted no benefit. Interestingly, LAV‐BPIFB4 ‐treated mice showed increased SDF‐1 levels in peripheral blood and myocardium and up‐regulation of the cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF‐1 up‐regulation was instrumental to LAV‐BPIFB4‐ induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF‐1 CXCR4 receptor. Conclusions In mice with type‐2 diabetes, LAV‐BPIFB4 gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes‐induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.