PMID- 32384208 OWN - NLM STAT- MEDLINE DCOM- 20210518 LR - 20240313 IS - 1879-0844 (Electronic) IS - 1388-9842 (Print) IS - 1388-9842 (Linking) VI - 22 IP - 9 DP - 2020 Sep TI - 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. PG - 1568-1581 LID - 10.1002/ejhf.1840 [doi] AB - 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. CI - (c) 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology. FAU - Dang, Zexu AU - Dang Z AD - Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Avolio, Elisa AU - Avolio E AD - Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Thomas, Anita C AU - Thomas AC AD - Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Faulkner, Ashton AU - Faulkner A AD - Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Beltrami, Antonio P AU - Beltrami AP AD - Department of Medicine, University of Udine, Udine, Italy. FAU - Cervellin, Celeste AU - Cervellin C AD - Department of Medicine, University of Udine, Udine, Italy. FAU - Carrizzo, Albino AU - Carrizzo A AD - Vascular Pathophysiology Unit, IRCCS Neuromed, Pozzilli, Italy. FAU - Maciag, Anna AU - Maciag A AD - Cardiovascular Department, IRCCS Multimedica, Milan, Italy. FAU - Gu, Yue AU - Gu Y AD - Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. FAU - Ciaglia, Elena AU - Ciaglia E AD - Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi (SA), Italy. FAU - Finato, Nicoletta AU - Finato N AD - Department of Medicine, University of Udine, Udine, Italy. FAU - Damato, Antonio AU - Damato A AD - Vascular Pathophysiology Unit, IRCCS Neuromed, Pozzilli, Italy. FAU - Spinetti, Gaia AU - Spinetti G AD - Cardiovascular Department, IRCCS Multimedica, Milan, Italy. FAU - Alenzi, Aishah AU - Alenzi A AD - PETIC, School of Medicine, University of Cardiff, Cardiff, UK. FAU - Paisey, Stephen J AU - Paisey SJ AD - PETIC, School of Medicine, University of Cardiff, Cardiff, UK. FAU - Vecchione, Carmine AU - Vecchione C AD - Vascular Pathophysiology Unit, IRCCS Neuromed, Pozzilli, Italy. AD - Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi (SA), Italy. FAU - Puca, Annibale A AU - Puca AA AD - Cardiovascular Department, IRCCS Multimedica, Milan, Italy. AD - Department of Medicine, Surgery and Dentistry, "Scuola Medica Salernitana", University of Salerno, Baronissi (SA), Italy. FAU - Madeddu, Paolo AU - Madeddu P AD - Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK. LA - eng GR - PG/18/38/33707/BHF_/British Heart Foundation/United Kingdom GR - PG/18/66/33838/BHF_/British Heart Foundation/United Kingdom GR - PG/15/54/31559/BHF_/British Heart Foundation/United Kingdom GR - RM/17/3/33381/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200508 PL - England TA - Eur J Heart Fail JT - European journal of heart failure JID - 100887595 RN - 0 (BPIFB4 protein, human) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Phosphoproteins) RN - 0 (Receptors, CXCR4) SB - IM CIN - Eur J Heart Fail. 2020 Sep;22(9):1582-1585. PMID: 32573029 MH - Animals MH - *Diabetes Mellitus, Experimental MH - *Diabetes Mellitus, Type 2/genetics MH - *Heart Failure/genetics/therapy MH - Humans MH - Intercellular Signaling Peptides and Proteins MH - Longevity MH - Mice MH - Mice, Obese MH - Myocardium MH - Obesity MH - Phosphoproteins MH - Receptors, CXCR4 MH - Signal Transduction PMC - PMC8220375 OTO - NOTNLM OT - BPIFB4 OT - Cardiomyopathy OT - Diabetes OT - Gene therapy OT - Longevity EDAT- 2020/05/10 06:00 MHDA- 2021/05/19 06:00 PMCR- 2020/05/08 CRDT- 2020/05/09 06:00 PHST- 2019/07/25 00:00 [received] PHST- 2020/04/08 00:00 [revised] PHST- 2020/04/10 00:00 [accepted] PHST- 2020/05/10 06:00 [pubmed] PHST- 2021/05/19 06:00 [medline] PHST- 2020/05/09 06:00 [entrez] PHST- 2020/05/08 00:00 [pmc-release] AID - EJHF1840 [pii] AID - 10.1002/ejhf.1840 [doi] PST - ppublish SO - Eur J Heart Fail. 2020 Sep;22(9):1568-1581. doi: 10.1002/ejhf.1840. Epub 2020 May 8.