Phosphoinositide 3-kinase [PI3K (p110α)] is able to negatively regulate the diabetes-induced increase in NADPH oxidase in the heart. Patients affected by diabetes exhibit significant cardiovascular morbidity and mortality, at least in part due to a cardiomyopathy characterized by oxidative stress and left ventricular (LV) dysfunction. Thus, PI3K (p110α) may represent a novel approach to protect the heart from diabetes-induced cardiac oxidative stress and dysfunction. In the present study, we investigated the therapeutic potential of a delayed intervention with cardiac-targeted PI3K gene therapy, administered to mice with established diabetes-induced LV diastolic dysfunction. Diabetes was induced in 6-week-old male mice by streptozotocin (STZ). After 8 weeks of untreated diabetes, LV diastolic dysfunction was confirmed by a reduction in echocardiography-derived transmitral E/A ratio. Diabetic and non-diabetic mice were randomly allocated to receive either recombinant adeno-associated viral vector-6 carrying a constitutively-active PI3K construct (recombinant adeno-associated-virus 6-constitutively active PI3K (p110α) (caPI3K) (rAAV6-caPI3K), single i.v. injection, 2 × 1011 vector genomes) or null vector, and were followed for a further 6 or 8 weeks. At study endpoint, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-caPI3K, administered 8 weeks after the induction of diabetes. Diabetes-induced impairments in each of LV NADPH oxidase, endoplasmic reticulum (ER) stress, apoptosis, cardiac fibrosis and cardiomyocyte hypertrophy, in addition to LV systolic dysfunction, were attenuated by delayed intervention with rAAV6-caPI3K. Hence, our demonstration that cardiac-targeted PI3K (p110α) gene therapy limits diabetes-induced up-regulation of NADPH oxidase and cardiac remodelling suggests new insights into promising approaches for the treatment of diabetic cardiomyopathy, at a clinically relevant time point (after diastolic dysfunction is manifested).
Skip Nav Destination
Article navigation
June 2017
-
Cover Image
Cover Image
The accompanying caption is: Image demonstrates a 3D reconstruction of the neurovascular unit in a hippocampal artery in the mouse brain. For further details, see article by Nizari et al in this issue, pages 1207-1214. Image kindly provided by Cheryl Hawkes.
Research Article|
June 07 2017
Phosphoinositide 3-kinase (p110α) gene delivery limits diabetes-induced cardiac NADPH oxidase and cardiomyopathy in a mouse model with established diastolic dysfunction
Darnel Prakoso;
Darnel Prakoso
*
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
2School of Biosciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Search for other works by this author on:
Miles J. De Blasio;
Miles J. De Blasio
*
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
2School of Biosciences, The University of Melbourne, Parkville, Victoria 3010, Australia
Search for other works by this author on:
Chengxue Qin;
Chengxue Qin
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
4Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia
Search for other works by this author on:
Sarah Rosli;
Sarah Rosli
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
Search for other works by this author on:
Helen Kiriazis;
Helen Kiriazis
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
Search for other works by this author on:
Hongwei Qian;
Hongwei Qian
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
Search for other works by this author on:
Xiao-Jun Du;
Xiao-Jun Du
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
5Department of Medicine, Monash University, Clayton, Victoria 3800, Australia
Search for other works by this author on:
Kate L. Weeks;
Kate L. Weeks
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
Search for other works by this author on:
Paul Gregorevic;
Paul Gregorevic
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
3Department of Physiology, The University of Melbourne, Parkville, Victoria 3010, Australia
7Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
8Department of Neurology, The University of Washington, Seattle, Washington 98195, U.S.A.
Search for other works by this author on:
Julie R. McMullen;
Julie R. McMullen
†
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
5Department of Medicine, Monash University, Clayton, Victoria 3800, Australia
6Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
Search for other works by this author on:
Rebecca H. Ritchie
Rebecca H. Ritchie
†
1Baker Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia
4Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria 3010, Australia
5Department of Medicine, Monash University, Clayton, Victoria 3800, Australia
Correspondence: Rebecca Ritchie ([email protected])
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
January 30 2017
Revision Received:
April 21 2017
Accepted:
May 08 2017
Accepted Manuscript online:
May 09 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (12): 1345–1360.
Article history
Received:
January 30 2017
Revision Received:
April 21 2017
Accepted:
May 08 2017
Accepted Manuscript online:
May 09 2017
Citation
Darnel Prakoso, Miles J. De Blasio, Chengxue Qin, Sarah Rosli, Helen Kiriazis, Hongwei Qian, Xiao-Jun Du, Kate L. Weeks, Paul Gregorevic, Julie R. McMullen, Rebecca H. Ritchie; Phosphoinositide 3-kinase (p110α) gene delivery limits diabetes-induced cardiac NADPH oxidase and cardiomyopathy in a mouse model with established diastolic dysfunction. Clin Sci (Lond) 1 June 2017; 131 (12): 1345–1360. doi: https://doi.org/10.1042/CS20170063
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Biochemical Society Member Sign in
Sign InSign in via your Institution
Sign in via your InstitutionGet Access To This Article
Open Access for all
We offer compliant routes for all authors from 2025. With library support, there will be no author nor reader charges in 5 journals. Check here |
![]() |