Effects of IGF-1 on<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mtext>I</mml:mtext><mml:mtext>K</mml:mtext></mml:msub></mml:mrow></mml:math>and<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:msub><mml:mtext>I</mml:mtext><mml:mtext>K1</mml:mtext></mml:msub></mml:mrow></mml:math>Channels via PI3K/Akt Signaling in Neonatal Cardiac Myocytes

Millis, Richard M.; Alvin, Zikiar; Zhao, Aiqiu; Haddad, Georges E.

doi:10.1155/2012/712153

Cited by 10 publications

(9 citation statements)

References 31 publications

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“…There is some evidence in vitro to suggest that IGF1R-PI3K-independent pathways can regulate electrical activity in the heart. In neonatal rat cardiac myocytes, IGF1 had an impact on potassium currents that protected myocytes against arrhythmogenesis, and this protection was mediated by both PI3K-dependent and PI3K-independent mechanisms 49 . Identification of drugs that can mediate protection independently of PI3K is of further significance because risk factors for HF and AF including obesity and diabetes have also been associated with impaired PI3K-Akt signalling in the heart [23][24][25]44 .…”

Section: Discussionmentioning

confidence: 96%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 96%

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

et al. 2014

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“…It has been documented that IGF-1 contributes to cardiac hypertrophy via activation of PI3K/Akt signaling [33]. As shown in Fig.…”

Section: Lyg-202-induced Apoptosis and Cell Cycle Arrest Via Modulatimentioning

confidence: 88%

LYG-202 exerts antitumor effect on PI3K/Akt signaling pathway in human breast cancer cells

et al. 2015

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In this study, we aimed to investigate the antitumor effect of LYG-202, a newly synthesized piperazine-substituted derivative of flavonoid on human breast cancer cells and illustrate the potential mechanisms. LYG-202 induced apoptosis in MCF-7, MDA-MB-231 and MDA-MB-435 cells. LYG-202 triggered the activation of mitochondrial apoptotic pathway through multiple steps: increasing Bax/Bcl-2 ratio, decreasing mitochondrial membrane potential (ΔΨ(m)), activating caspase-9 and caspase-3, inducing cleavage of poly(ADP-ribose) polymerase, cytochrome c release and apoptosis-inducing factor translocation. Furthermore, LYG-202 inhibited cell cycle progression at the G1/S transition via targeting Cyclin D, CDK4 and p21(Waf1/Cip1). Additionally, LYG-202 increased the generation of intracellular ROS. N-Acetyl cysteine, an antioxidant, reversed LYG-202-induced apoptosis suggesting that LYG-202 induces apoptosis by accelerating ROS generation. Further, we found that LYG-202 deactivated the PI3K/Akt pathway, activated Bad phosphorylation, increased Cyclin D and Bcl-xL expression, and inhibited NF-κB nuclear translocation. Activation of PI3K/Akt pathway by IGF-1 attenuated LYG-202-induced apoptosis and cell cycle arrest. Our in vivo study showed that LYG-202 exhibited a potential antitumor effect in nude mice inoculated with MCF-7 tumor through similar mechanisms identified in cultured cells. In summary, our results demonstrated that LYG-202 induced apoptosis and cell cycle arrest via targeting PI3K/Akt pathway, indicating that LYG-202 is a potential anticancer agent for breast cancer.

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“…Acute treatment of rat ventricular myocytes with IGF-1, induction of volume-overload cardiac hypertrophy (which is associated with increased IGF-1 signaling and Akt activation) or adenoviral expression of Akt or constitutively active PI3K in rat neonatal cardiomyocytes were all reported to decrease the delayed rectifier current I K and the inward rectifier I K1 . 76, 77 On the other hand, repolarizing potassium currents in ventricular myocytes were upregulated in two models of physiological hypertrophy, one produced by cardiac-specific expression of constitutively active p110α and the other by swim training. 78 Protein and/or mRNA expression of numerous potassium channel subunits was also increased (Fig.…”

Section: Voltage-dependent Potassium Channelsmentioning

confidence: 99%

Control of Cardiac Repolarization by Phosphoinositide 3-Kinase Signaling to Ion Channels

Ballou

Lin

Cohen

2015

Circulation Research

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Upregulation of phosphoinositide 3-kinase (PI3K) signaling is a common alteration in human cancer, and numerous drugs that target this pathway have been developed for cancer treatment. However, recent studies have implicated inhibition of the PI3K signaling pathway as the cause of a drug-induced long QT syndrome in which alterations in several ion currents contribute to arrhythmogenic drug activity. Surprisingly, some drugs that were thought to induce long QT syndrome by direct block of the rapid delayed rectifier (IKr) also appear to inhibit PI3K signaling, an effect that may contribute to their arrhythmogenicity. The importance of PI3K in regulating cardiac repolarization is underscored by evidence that QT interval prolongation in diabetes also may result from changes in multiple currents due to decreased insulin activation of PI3K in the heart. How PI3K signaling regulates ion channels to control the cardiac action potential is poorly understood. Hence, this review summarizes what is known about the impact of PI3K and its downstream effectors including Akt on sodium, potassium and calcium currents in cardiac myocytes. We also refer to some studies in non-cardiac cells that provide insight into potential mechanisms of ion channel regulation by this signaling pathway in the heart. Drug development and safety could be improved with a better understanding of the mechanisms by which PI3K regulates cardiac ion channels and the extent to which PI3K inhibition contributes to arrhythmogenic susceptibility.

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Effects of IGF-1 onIKandIK1Channels via PI3K/Akt Signaling in Neonatal Cardiac Myocytes

Cited by 10 publications

References 31 publications

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

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

LYG-202 exerts antitumor effect on PI3K/Akt signaling pathway in human breast cancer cells

Control of Cardiac Repolarization by Phosphoinositide 3-Kinase Signaling to Ion Channels

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