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Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy

Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu....

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Autores principales: Tate, Mitchel, Perera, Nimna, Prakoso, Darnel, Willis, Andrew M., Deo, Minh, Oseghale, Osezua, Qian, Hongwei, Donner, Daniel G, Kiriazis, Helen, De Blasio, Miles J., Gregorevic, Paul, Ritchie, Rebecca H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532155/
https://www.ncbi.nlm.nih.gov/pubmed/34690762
http://dx.doi.org/10.3389/fphar.2021.719290
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author Tate, Mitchel
Perera, Nimna
Prakoso, Darnel
Willis, Andrew M.
Deo, Minh
Oseghale, Osezua
Qian, Hongwei
Donner, Daniel G
Kiriazis, Helen
De Blasio, Miles J.
Gregorevic, Paul
Ritchie, Rebecca H.
author_facet Tate, Mitchel
Perera, Nimna
Prakoso, Darnel
Willis, Andrew M.
Deo, Minh
Oseghale, Osezua
Qian, Hongwei
Donner, Daniel G
Kiriazis, Helen
De Blasio, Miles J.
Gregorevic, Paul
Ritchie, Rebecca H.
author_sort Tate, Mitchel
collection PubMed
description Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.
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spelling pubmed-85321552021-10-23 Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy Tate, Mitchel Perera, Nimna Prakoso, Darnel Willis, Andrew M. Deo, Minh Oseghale, Osezua Qian, Hongwei Donner, Daniel G Kiriazis, Helen De Blasio, Miles J. Gregorevic, Paul Ritchie, Rebecca H. Front Pharmacol Pharmacology Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart. Frontiers Media S.A. 2021-10-08 /pmc/articles/PMC8532155/ /pubmed/34690762 http://dx.doi.org/10.3389/fphar.2021.719290 Text en Copyright © 2021 Tate, Perera, Prakoso, Willis, Deo, Oseghale, Qian, Donner, Kiriazis, De Blasio, Gregorevic and Ritchie. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Tate, Mitchel
Perera, Nimna
Prakoso, Darnel
Willis, Andrew M.
Deo, Minh
Oseghale, Osezua
Qian, Hongwei
Donner, Daniel G
Kiriazis, Helen
De Blasio, Miles J.
Gregorevic, Paul
Ritchie, Rebecca H.
Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
title Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
title_full Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
title_fullStr Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
title_full_unstemmed Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
title_short Bone Morphogenetic Protein 7 Gene Delivery Improves Cardiac Structure and Function in a Murine Model of Diabetic Cardiomyopathy
title_sort bone morphogenetic protein 7 gene delivery improves cardiac structure and function in a murine model of diabetic cardiomyopathy
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8532155/
https://www.ncbi.nlm.nih.gov/pubmed/34690762
http://dx.doi.org/10.3389/fphar.2021.719290
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