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The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice

Venardos, Kylie, De Jong, Kirstie A., Elkamie, Mansour, Connor, Timothy and McGee, Sean L. 2015, The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice, PLoS one, vol. 10, no. 3, pp. 1-14, doi: 10.1371/journal.pone.0120934.

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Title The PKD inhibitor CID755673 enhances cardiac function in diabetic db/db mice
Author(s) Venardos, Kylie
De Jong, Kirstie A.
Elkamie, Mansour
Connor, Timothy
McGee, Sean L.
Journal name PLoS one
Volume number 10
Issue number 3
Article ID e0120934
Start page 1
End page 14
Total pages 14
Publisher PLoS
Place of publication San Francisco, Calif.
Publication date 2015
ISSN 1932-6203
Keyword(s) Animals
Azepines
Benzofurans
Diabetes Mellitus, Type 2
Diabetic Cardiomyopathies
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Activation
Heart
Male
Mice
Myocardium
Organ Size
Phosphorylation
Protein Kinase C
Protein Kinase Inhibitors
Transcriptome
Ventricular Dysfunction
Ventricular Function, Left
Summary The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy.
Language eng
DOI 10.1371/journal.pone.0120934
Field of Research MD Multidisciplinary
Copyright notice ©2015, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30074911

Document type: Journal Article
Collections: School of Medicine
Open Access Collection
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Created: Fri, 14 Aug 2015, 09:31:46 EST

Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.