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- W2041932820 abstract "The fast transient outward potassium current (Ito,f), which is carried by voltage-gated Kv4.2 and Kv4.3 potassium channels and auxiliary subunit KChIP2, plays a critical role in early repolarization of the cardiac action potential. Ito,f and its gene products are strongly down-regulated in cardiac hypertrophy and disease, leading to altered excitation-contraction coupling and electrical activity as well as hypertrophy. Despite the importance of Ito,f in normal and diseased hearts, the regulation of Ito,f remains poorly understood. Studies have shown that the biologically active sphingolipid, sphingosine-1-phosphate (S1P), induces cardiac hypertrophy. In addition, the inflammatory pro-hypertrophic cytokine TNF-alpha, which decreases Ito,f, activates sphingosine kinase 1, the highly regulated enzyme that produces S1P. Therefore, we investigated the role of TNF-alpha and S1P signaling in mediating the down-regulation of Ito,f. In cultured neonatal myocytes, the TNF-alpha inhibitor etanercept attenuated reductions in Ito,f current density that were caused by the hypertrophic agonist phenylephrine (PE). Inhibition of sphingosine kinases by dimethylsphingosine prevented reductions in Ito,f that were caused by PE. Furthermore, application of S1P reduced Ito,f current density and caused hypertrophy. To interrogate the down-stream events involved in TNF-alpha/S1P- induced reductions in Ito,f, we focused on NF-kappaB since it is one of TNF-alpha's principal down-stream effectors and a major player in cardiac hypertrophy. Inhibition of NF-kappaB signaling, via an adenoviral expression of an IkappaB-alpha dominant negative mutant, prevented Ito,f reductions caused by S1P, TNF-alpha and PE. Taken together, the data suggests a linear pathway whereby PE promotes the shedding of TNF-alpha, which activates sphingosine kinase and elevates S1P, leading to activation of NF-kappaB and down-regulation of Ito,f.We will test this model in future experiments by assessing the effects of cardiac disease on Ito,f in knockout mice lacking sphingosine kinase and TNF-alpha." @default.
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- W2041932820 date "2010-01-01" @default.
- W2041932820 modified "2023-09-27" @default.
- W2041932820 title "Regulation of the Transient Outward Potassium Current Itof in Cardiac Hypertrophy by Sphingosine-1-Phosphate Signaling" @default.
- W2041932820 doi "https://doi.org/10.1016/j.bpj.2009.12.2884" @default.
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