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

Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110 alpha) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110 alpha) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110 alpha) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes. Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110 alpha) activity (constitutively active PI3K [p110 alpha], caPI3K] or decreased PI3K(p110 alpha) activity (dominant-negative PI3K [p110 alpha], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed. 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 beta 2 (PKC beta 2), p22 (phox) and apoptosis signal-regulating 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, PKC beta 2, Ask1 and p22 (phox) expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110 alpha) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function. These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110 alpha) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.