PMID:23393573

Citation	Kaur, K, Zarzoso, M, Ponce-Balbuena, D, Guerrero-Serna, G, Hou, L, Musa, H and Jalife, J (2013) TGF-β1, released by myofibroblasts, differentially regulates transcription and function of sodium and potassium channels in adult rat ventricular myocytes. PLoS ONE 8:e55391
Abstract	Cardiac injury promotes fibroblasts activation and differentiation into myofibroblasts, which are hypersecretory of multiple cytokines. It is unknown whether any of such cytokines are involved in the electrophysiological remodeling of adult cardiomyocytes. We cultured adult cardiomyocytes for 3 days in cardiac fibroblast conditioned medium (FCM) from adult rats. In whole-cell voltage-clamp experiments, FCM-treated myocytes had 41% more peak inward sodium current (I(Na)) density at -40 mV than myocytes in control medium (p<0.01). In contrast, peak transient outward current (I(to)) was decreased by ∼55% at 60 mV (p<0.001). Protein analysis of FCM demonstrated that the concentration of TGF-β1 was >3 fold greater in FCM than control, which suggested that FCM effects could be mediated by TGF-β1. This was confirmed by pre-treatment with TGF-β1 neutralizing antibody, which abolished the FCM-induced changes in both I(Na) and I(to). In current-clamp experiments TGF-β1 (10 ng/ml) prolonged the action potential duration at 30, 50, and 90 repolarization (p<0.05); at 50 ng/ml it gave rise to early afterdepolarizations. In voltage-clamp experiments, TGF-β1 increased I(Na) density in a dose-dependent manner without affecting voltage dependence of activation or inactivation. I(Na) density was -36.25±2.8 pA/pF in control, -59.17±6.2 pA/pF at 0.1 ng/ml (p<0.01), and -58.22±6.6 pA/pF at 1 ng/ml (p<0.01). In sharp contrast, I(to) density decreased from 22.2±1.2 pA/pF to 12.7±0.98 pA/pF (p<0.001) at 10 ng/ml. At 1 ng/ml TGF-β1 significantly increased SCN5A (Na(V)1.5) (+73%; p<0.01), while reducing KCNIP2 (Kchip2; -77%; p<0.01) and KCND2 (K(V)4.2; -50% p<0.05) mRNA levels. Further, the TGF-β1-induced increase in I(Na) was mediated through activation of the PI3K-AKT pathway via phosphorylation of FOXO1 (a negative regulator of SCN5A). TGF-β1 released by myofibroblasts differentially regulates transcription and function of the main cardiac sodium channel and of the channel responsible for the transient outward current. The results provide new mechanistic insight into the electrical remodeling associated with myocardial injury.
Links	PubMed PMC3564808 Online version:10.1371/journal.pone.0055391
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:TGFB1		GO:0006468: protein phosphorylation	ECO:0000314:		P		According to Figure 8b, there was a 67%increase in phosphorylated FOXO1 in TGF- beta 1 treated cells compared to the levels in control treated cells. Moreover, Phosphorylation of FOXO1 in TGF-Beta 1 treated cells was inhibited in cells pretreated with P13K inhibitor.	complete CACAO 7662
RAT:TGFB1	involved_in	GO:0006468: protein phosphorylation	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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