Reduced phosphoinositide 3-kinase (p110alpha) activation increases the susceptibility to atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments. A limited understanding of the molecular mechanisms responsible for the development of AF has hindered treatment strategies. The purpose of this study was to assess whether reduced activation of phosphoinositide 3-kinase (PI3K, p110alpha) makes the compromised heart susceptible to AF. Risk factors for AF, including aging, obesity, and diabetes, have been associated with insulin resistance that leads to depressed/defective PI3K signaling. However, to date, there has been no link between PI3K(p110alpha) and AF. To address this question, we crossed a cardiac-specific transgenic mouse model of dilated cardiomyopathy (DCM) with a cardiac-specific transgenic mouse expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity). Adult ( approximately 4.5 months) double-transgenic (dnPI3K-DCM), single-transgenic (DCM-Tg, dnPI3K-Tg), and nontransgenic mice were subjected to morphological, functional/ECG, microarray, and biochemical analyses. dnPI3K-DCM mice developed AF and had depressed cardiac function as well as greater atrial enlargement and fibrosis than DCM-Tg mice. AF was not detected in other groups. Aged DCM-Tg mice ( approximately 15 months) with a similar phenotype to dnPI3K-DCM mice (4.5 months) did not develop AF, suggesting loss of PI3K activity directly contributed to the AF phenotype. Furthermore, increasing PI3K activity reduced atrial fibrosis and improved cardiac conduction in DCM-Tg mice. Finally, in atrial appendages from patients with AF, PI3K activation was lower compared with tissue from patients in sinus rhythm. These results suggest a link between PI3K(p110alpha) and AF.

The protective effects of exercise and phosphoinositide 3-kinase (p110alpha) in the failing heart.

Despite the development of a wide range of therapies, heart failure remains a leading cause of death in Western society. New therapies are needed to help combat this debilitating condition. Exercise is becoming an increasingly important feature of rehabilitation programmes for patients with heart failure. Before the 1980s, patients with heart failure were advised not to exercise as it was thought that exercise would increase the risk of a cardiac event (such as myocardial infarction). However, in recent years both aerobic and resistance training have been shown to be safe and beneficial for patients with heart failure, improving exercise tolerance and quality of life, and preventing muscular deconditioning. The molecular mechanisms responsible for exercise-induced cardioprotection are yet to be elucidated, however studies in transgenic mice have identified PI3K(p110alpha) (phosphoinositide 3-kinase p110alpha) as a likely mediator. PI3K(p110alpha) is a lipid kinase which is activated in the heart during chronic exercise training, and is important for maintaining heart structure and function in various pathological settings. In the present review the protective effects of PI3K(p110alpha) in the failing heart and its potential as a therapeutic strategy for the treatment of heart failure is discussed.

Promoting physiological hypertrophy in the failing heart.

1. Heart failure rates have reached epidemic proportions in Western society. 2. New strategies proposed to improve cardiac function of the failing heart include regeneration, stem cell therapy, innovative methods for the revascularization of ischaemic cardiac tissue and the activation of signalling pathways that promote physiological growth (hypertrophy). 3. The insulin-like growth factor 1-phosphoinositide-3-kinase pathway is a well characterized regulator of physiological hypertrophy. 4. In this mini-review we present studies that suggest promoting physiological hypertrophy in the failing heart may be beneficial.

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice.

Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

Molecular distinction between physiological and pathological cardiac hypertrophy: experimental findings and therapeutic strategies.

Cardiac hypertrophy can be defined as an increase in heart mass. Pathological cardiac hypertrophy (heart growth that occurs in settings of disease, e.g. hypertension) is a key risk factor for heart failure. Pathological hypertrophy is associated with increased interstitial fibrosis, cell death and cardiac dysfunction. In contrast, physiological cardiac hypertrophy (heart growth that occurs in response to chronic exercise training, i.e. the 'athlete's heart') is reversible and is characterized by normal cardiac morphology (i.e. no fibrosis or apoptosis) and normal or enhanced cardiac function. Given that there are clear functional, structural, metabolic and molecular differences between pathological and physiological hypertrophy, a key question in cardiovascular medicine is whether mechanisms responsible for enhancing function of the athlete's heart can be exploited to benefit patients with pathological hypertrophy and heart failure. This review summarizes key experimental findings that have contributed to our understanding of pathological and physiological heart growth. In particular, we focus on signaling pathways that play a causal role in the development of pathological and physiological hypertrophy. We discuss molecular mechanisms associated with features of cardiac hypertrophy, including protein synthesis, sarcomeric organization, fibrosis, cell death and energy metabolism and provide a summary of profiling studies that have examined genes, microRNAs and proteins that are differentially expressed in models of pathological and physiological hypertrophy. How gender and sex hormones affect cardiac hypertrophy is also discussed. Finally, we explore how knowledge of molecular mechanisms underlying pathological and physiological hypertrophy may influence therapeutic strategies for the treatment of cardiovascular disease and heart failure.

Role of phosphoinositide 3-kinases in regulating cardiac function.

Phosphoinositide 3-kinases (PI3Ks) are important signaling proteins in the heart. Class IA PI3Ks (p110alpha, beta) are critical regulators of physiological heart growth and cell survival, and are generally considered to be beneficial for heart function. In contrast, activation of class IB PI3K(p110gamma) is detrimental for heart function, reducing cardiac contractility. This may have implications for the treatment of heart disease and failure. In vitro, ex vivo and in vivo studies have contributed to our understanding of PI3K signaling in the heart. This review summarizes class I PI3K signaling in the regulation of cardiac function, with a particular focus on the role of different PI3K isoforms in settings of heart disease.

Protein kinase C promotes restoration of calcium homeostasis to platelet activating factor-stimulated human neutrophils by inhibition of phospholipase C.

BACKGROUND: The role of protein kinase C (PKC) in regulating the activity of phospholipase C (PLC) in neutrophils activated with the chemoattractant, platelet-activating factor (PAF, 20 and 200 nM), was probed in the current study using the selective PKC inhibitors, GF10903X (0.5 - 1 muM) and staurosporine (400 nM). METHODS: Alterations in cytosolic Ca2+, Ca2+ influx, inositol triphosphate (IP3), and leukotriene B4 production were measured using spectrofluorimetric, radiometric and competitive binding radioreceptor and immunoassay procedures, respectively. RESULTS: Activation of the cells with PAF was accompanied by an abrupt increase in cytosolic Ca2+ followed by a gradual decline towards basal levels. Pretreatment of neutrophils with the PKC inhibitors significantly increased IP3 production with associated enhanced Ca2+ release from storage vesicles, prolongation of the peak cytosolic Ca2+ transients, delayed clearance and exaggerated reuptake of the cation, and markedly increased synthesis of LTB4. The alterations in Ca2+ fluxes observed with the PKC inhibitors were significantly attenuated by U73122, a PLC inhibitor, as well as by cyclic AMP-mediated upregulation of the Ca2+-resequestering endomembrane ATPase.Taken together, these observations are compatible with a mechanism whereby PKC negatively modulates the activity of PLC, with consequent suppression of IP3 production and down-regulation of Ca2+ mediated pro-inflammatory responses of PAF-activated neutrophils. CONCLUSION: Although generally considered to initiate and/or amplify intracellular signalling cascades which activate and sustain the pro-inflammatory activities of neutrophils and other cell types, the findings of the current study have identified a potentially important physiological, anti-inflammatory function for PKC, at least in neutrophils.