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Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes


Ritchie, RH and Love, JE and Huynh, K and Bernardo, BC and Henstridge, DC and Kiriazis, H and Tham, YK and Sapra, G and Qin, C and Cemerlang, N and Boey, EJH and Jandeleit-Dahm, K and Du, X-J and McMullen, JR, Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes, Diabetologia, 55, (12) pp. 3369-3381. ISSN 0012-186X (2012) [Refereed Article]

Copyright Statement

Copyright 2012 Springer-Verlag

DOI: doi:10.1007/s00125-012-2720-0


Aims/hypothesis: Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.

Methods: Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominantnegative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed.

Results: Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 phox and apoptosis signalregulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function.

Conclusions/interpretation: These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.

Item Details

Item Type:Refereed Article
Keywords:diabetes, fibrosis, hypertrophy, left ventricular function, myocardium; NADPH oxidase, PI3K, PKC2, reactive oxygen species, atrial natriuretic factor, brain natriuretic peptide, hemoglobin A1c, phosphatidylinositol 3 kinase, protein kinase B, male
Research Division:Biological Sciences
Research Group:Biochemistry and cell biology
Research Field:Signal transduction
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Henstridge, DC (Dr Darren Henstridge)
ID Code:133338
Year Published:2012
Web of Science® Times Cited:68
Deposited By:Health Sciences
Deposited On:2019-06-24
Last Modified:2019-07-23

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