Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene

Ashton R M Faulkner; Zexu Dang; Elisa Avolio; Anita C Thomas; Thomas E Batstone; Gavin R Lloyd; Ralf Weber; Lukas Najdekr; Andris Jankevics; Warwick Dunn; Gaia Spinetti; Carmine Vecchione; Annibale Alessandro Puca; Paolo R Madeddu

doi:10.3390/cells9051283

Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene

Ashton R M Faulkner
, Zexu Dang
, Elisa Avolio
, Anita C Thomas
, Thomas E Batstone
, Gavin R Lloyd
, Ralf Weber
, Lukas Najdekr
, Andris Jankevics
, Warwick Dunn
, Gaia Spinetti
, Carmine Vecchione
, Annibale Alessandro Puca
, Paolo R Madeddu^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

16 Citations (Scopus)

143 Downloads (Pure)

Abstract

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 metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptomics (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 8 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.

Original language	English
Article number	1283
Number of pages	5
Journal	Cells
Volume	9
Issue number	5
DOIs	https://doi.org/10.3390/cells9051283
Publication status	Published - 21 May 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Groups and Themes

Bristol Heart Institute

Keywords

cardiomyopathy
type-2 diabetes
longevity
gene therapy
BPIFB4

Access to Document

10.3390/cells9051283

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Final published version, 3.83 MBLicence: CC BY

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Longevity-associated BPIFB4 gene therapy for treatment of ischemic disease
Madeddu, P. R. (Principal Investigator)
1/08/15 → 31/07/18
Project: Research

Cite this

Faulkner, A. R. M., Dang, Z., Avolio, E., Thomas, A. C., Batstone, T. E., Lloyd, G. R., Weber, R., Najdekr, L., Jankevics, A., Dunn, W., Spinetti, G., Vecchione, C., Puca, A. A., & Madeddu, P. R. (2020). Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene. Cells, 9(5), Article 1283. https://doi.org/10.3390/cells9051283

@article{7165819441624071a99f5d2874aa0a46,

title = "Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene",

abstract = "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 metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptomics (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 8 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.",

keywords = "cardiomyopathy, type-2 diabetes, longevity, gene therapy, BPIFB4",

author = "Faulkner, \{Ashton R M\} and Zexu Dang and Elisa Avolio and Thomas, \{Anita C\} and Batstone, \{Thomas E\} and Lloyd, \{Gavin R\} and Ralf Weber and Lukas Najdekr and Andris Jankevics and Warwick Dunn and Gaia Spinetti and Carmine Vecchione and Puca, \{Annibale Alessandro\} and Madeddu, \{Paolo R\}",

year = "2020",

month = may,

day = "21",

doi = "10.3390/cells9051283",

language = "English",

volume = "9",

journal = "Cells",

issn = "2073-4409",

publisher = "MDPI AG",

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Faulkner, ARM, Dang, Z, Avolio, E, Thomas, AC, Batstone, TE, Lloyd, GR, Weber, R, Najdekr, L, Jankevics, A, Dunn, W, Spinetti, G, Vecchione, C, Puca, AA & Madeddu, PR 2020, 'Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene', Cells, vol. 9, no. 5, 1283. https://doi.org/10.3390/cells9051283

TY - JOUR

T1 - Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene

AU - Faulkner, Ashton R M

AU - Dang, Zexu

AU - Avolio, Elisa

AU - Thomas, Anita C

AU - Batstone, Thomas E

AU - Lloyd, Gavin R

AU - Weber, Ralf

AU - Najdekr, Lukas

AU - Jankevics, Andris

AU - Dunn, Warwick

AU - Spinetti, Gaia

AU - Vecchione, Carmine

AU - Puca, Annibale Alessandro

AU - Madeddu, Paolo R

PY - 2020/5/21

Y1 - 2020/5/21

N2 - 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 metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptomics (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 8 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.

AB - 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 metabolic phenotype (ultra-high-performance liquid chromatography-mass spectrometry, UHPLC-MS) and cardiac transcriptomics (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 8 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.

KW - cardiomyopathy

KW - type-2 diabetes

KW - longevity

KW - gene therapy

KW - BPIFB4

U2 - 10.3390/cells9051283

DO - 10.3390/cells9051283

M3 - Article (Academic Journal)

C2 - 32455800

SN - 2073-4409

VL - 9

JO - Cells

JF - Cells

IS - 5

M1 - 1283

ER -

Multi-omics analysis of diabetic heart disease in the db/db model reveals potential targets for treatment by a longevity-associated gene

Abstract

UN SDGs

Research Groups and Themes

Keywords

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Projects

Longevity-associated BPIFB4 gene therapy for treatment of ischemic disease

Cite this