Akt1 Is Required for Physiological Cardiac Growth

DeBosch, Brian J.; Treskov, Iya; Lupu, Traian S.; Weinheimer, Carla J.; Kovács, Attila; Courtois, Michael; Muslin, Anthony J.

doi:10.1161/circulationaha.105.595231

Cited by 482 publications

(430 citation statements)

References 32 publications

Supporting

Mentioning

391

Contrasting

Unclassified

Order By: Relevance

“…Increased pAKT was maintained in hearts of diabetic caPI3K-Tg mice, and AKT was previously shown to directly inhibit apoptosis signal-regulating kinase 1 (ASK1) in response to oxidative stress [43]. Further, AKT1 or deficiency of ASK1 protects the heart against cardiac pathology [44][45][46]. Thus, PI3K (p110α) is likely to mediate protection, in part, by activation of AKT.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

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 p22 phox 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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Both Akt1 and Akt2 isoforms are highly expressed in heart (Muslin and DeBosch, 2006), with Akt1 essential to normal cardiac growth (Cho et al, 2001b) and physiological hypertrophy (DeBosch et al, 2006b), and Akt2 involved in insulin-regulated glucose homeostasis and cardiomyocyte survival (Cho et al, 2001a;Garofalo et al, 2003;Etzion et al, 2010). Knockout of Akt2 results in severe hyperglycaemia (Cho et al, 2001a) and evidence of diabetic cardiomyopathy (Etzion et al, 2010).…”

Section: Protein Kinase B/aktmentioning

confidence: 99%

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Reichelt

O’Brien

Thomas

et al. 2017

The International Journal of Biochemistry & Cell Biology

View full text Add to dashboard Cite

“…Transgenic overexpression of PI3K [30], IGF-1 [31], or the IGF-1 receptor [29], resulting in higher Akt activity, are accompanied by preserved cardiac function. Furthermore, activation of Akt has a pivotal regulatory role for normal postnatal growth of the heart [11].…”

Section: Discussionmentioning

confidence: 99%

“…The molecular mechanisms determining the difference between physiological and pathological hypertrophy are still poorly understood. Whereas some authors hypothesize distinct signalling systems for the different types of hypertrophy [1,[10][11][12], there is now growing evidence that identical pathways can induce both, adaptive and maladaptive hypertrophy, depending on the intensity and duration of their activation [13,[13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

Jacobshagen

Grüber

Teucher

et al. 2008

European J of Heart Fail

View full text Add to dashboard Cite

In human hearts, the transition from cardiac hypertrophy to advanced heart failure (HF) is accompanied by a tremendous increase in Akt phosphorylation. In non-myocardial tissue, the cyclooxygenase (COX)-2 inhibitor celecoxib has been shown to COX-independently inhibit Akt signalling.We studied the effects of celecoxib on Akt signalling and hypertrophic response in myocardium. In rabbit isolated cardiac myocytes celecoxib concentration-dependently (10-100 μmol/L) inhibited the insulin-induced increase in phosphorylation of Akt and its downstream targets, GSK-3β and p70 S6 kinase, by reducing the phosphorylation level of the upstream regulator PTEN. Inhibition of Akt signalling was accompanied by a significant suppression of characteristic features of cardiac hypertrophy: Celecoxib concentration-dependently suppressed the agonist-induced enhancement of total protein synthesis and BNP mRNA expression.In mice (C57BL/6NCrl) subjected to left ventricular (LV) pressure overload by aortic banding, celecoxib treatment (50 mg•kg − 1 •d − 1 ) significantly attenuated LV dilation and contractile dysfunction compared with placebo-treated mice. Moreover, celecoxib significantly reduced mortality 8 weeks after banding.Thus, celecoxib can be used to titrate Akt signalling and hypertrophic response in myocardium. It reduces load-induced LV dilation, contractile dysfunction and mortality in vivo. This may have clinical implications for the prevention and treatment of maladaptive hypertrophy and its progression to HF in humans.

show abstract

Akt1 Is Required for Physiological Cardiac Growth

Cited by 482 publications

References 32 publications

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

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

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

Celecoxib modulates hypertrophic signalling and prevents load‐induced cardiac dysfunction

Contact Info

Product

Resources

About