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Open AccessArticle

Multi-Omics Analysis of Diabetic Heart Disease in the db/db Model Reveals Potential Targets for Treatment by a Longevity-Associated Gene

1
Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol BS2 8HW UK
2
School of Biological Sciences, University of Bristol, Bristol BS1 5QD, UK
3
Phenome Centre Birmingham, University of Birmingham, Birmingham B15 2TT, UK
4
School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK
5
Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, B15 2TQ, UK
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IRCCS Multimedica, Cardiovascular Department, 20138 Milan, Italy
7
Department of Medicine, University of Salerno, 84081 Baronissi, Italy
8
IRCCS Neuromed, Department of Vascular Physiopathology, 86077 Pozzilli, Italy
*
Author to whom correspondence should be addressed.
Authors with equal contribution.
Cells 2020, 9(5), 1283; https://doi.org/10.3390/cells9051283
Received: 20 April 2020 / Revised: 14 May 2020 / Accepted: 18 May 2020 / Published: 21 May 2020
(This article belongs to the Special Issue Stem Cell-Immune Function and Cardiac Regeneration)
Characterisation of animal models of diabetic cardiomyopathy may help unravel new molecular targets for therapy. Long-living individuals are protected from the adverse influence of diabetes on the heart, and the transfer of a longevity-associated variant (LAV) of the human BPIFB4 gene protects cardiac function in the db/db mouse model. This study aimed to determine the effect of LAV-BPIFB4 therapy on the metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptome (next-generation RNAseq) in db/db mice. UHPLC-MS showed that 493 cardiac metabolites were differentially modulated in diabetic compared with non-diabetic mice, mainly related to lipid metabolism. Moreover, only 3 out of 63 metabolites influenced by LAV-BPIFB4 therapy in diabetic hearts showed a reversion from the diabetic towards the non-diabetic phenotype. RNAseq showed 60 genes were differentially expressed in hearts of diabetic and non-diabetic mice. The contrast between LAV-BPIFB4- and vehicle-treated diabetic hearts revealed eight genes differentially expressed, mainly associated with mitochondrial and metabolic function. Bioinformatic analysis indicated that LAV-BPIFB4 re-programmed the heart transcriptome and metabolome rather than reverting it to a non-diabetic phenotype. Beside illustrating global metabolic and expressional changes in diabetic heart, our findings pinpoint subtle changes in mitochondrial-related proteins and lipid metabolism that could contribute to LAV-BPIFB4-induced cardio-protection in a murine model of type-2 diabetes. View Full-Text
Keywords: cardiomyopathy; type-2 diabetes; longevity; gene therapy; BPIFB4 cardiomyopathy; type-2 diabetes; longevity; gene therapy; BPIFB4
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MDPI and ACS Style

Faulkner, A.; Dang, Z.; Avolio, E.; Thomas, A.C.; Batstone, T.; Lloyd, G.R.; Weber, R.J.; Najdekr, L.; Jankevics, A.; Dunn, W.B.; Spinetti, G.; Vecchione, C.; Puca, A.A.; Madeddu, P. Multi-Omics Analysis of Diabetic Heart Disease in the db/db Model Reveals Potential Targets for Treatment by a Longevity-Associated Gene. Cells 2020, 9, 1283.

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