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Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP
Ho-Jin Park, … , Mark S. Link, Jonas B. Galper
Ho-Jin Park, … , Mark S. Link, Jonas B. Galper
Published December 3, 2007
Citation Information: J Clin Invest. 2008;118(1):259-271. https://doi.org/10.1172/JCI32011.
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Research Article Cardiology

Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP

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Abstract

Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein–coupled inward rectifying K+ channel GIRK1/4 and results in an acetylcholine-sensitive K+ current, IKACh. We describe a unique relationship between lipid homeostasis, the lipid-sensitive transcription factor SREBP-1, regulation of the cardiac parasympathetic response, and the development of ventricular arrhythmia. In embryonic chick atrial myocytes, lipid lowering by culture in lipoprotein-depleted serum increased SREBP-1 levels, GIRK1 expression, and IKACh activation. Regulation of the GIRK1 promoter by SREBP-1 and lipid lowering was dependent on interaction with 2 tandem sterol response elements and an upstream E-box motif. Expression of dominant negative SREBP-1 (DN–SREBP-1) reversed the effect of lipid lowering on IKACh and GIRK1. In SREBP-1 knockout mice, both the response of the heart to parasympathetic stimulation and the expression of GIRK1 were reduced compared with WT. IKACh, attenuated in atrial myocytes from SREBP-1 knockout mice, was stimulated by SREBP-1 expression. Following myocardial infarction, SREBP-1 knockout mice were twice as likely as WT mice to develop ventricular tachycardia in response to programmed ventricular stimulation. These results demonstrate a relationship between lipid metabolism and parasympathetic response that may play a role in arrhythmogenesis.

Authors

Ho-Jin Park, Serban P. Georgescu, Chuang Du, Christopher Madias, Mark J. Aronovitz, C. Michael Welzig, Bo Wang, Ulrike Begley, Yali Zhang, Robert O. Blaustein, Richard D. Patten, Richard H. Karas, Herbert H. Van Tol, Timothy F. Osborne, Hitoshi Shimano, Ronglih Liao, Mark S. Link, Jonas B. Galper

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Figure 2

Cis-acting elements required for SREBP regulation of the GIRK1 promoter.

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Cis-acting elements required for SREBP regulation of the GIRK1 promoter....
(A) Specificity of SREBP stimulation of GIRK1 promoter activity. Atrial myocytes were cotransfected with a construct containing 1.6 kb of the GIRK1 promoter reporter and increasing amounts of a construct expressing either SREBP-1a, -1c, or -2. (B) Upper panel: Nucleotide sequence of the GIRK1 promoter from –1070 to –1209. Lower panel: Deletion constructs of the GIRK1 promoter. (C and D) Effect of deletion mutants of the GIRK1 promoter on SREBP-1a stimulation of promoter activity. Data are plotted as fold stimulation above basal level of the p30 promoter in the absence of SREBP-1a, taken as 1. Data represent the mean of 4 determinations carried out in triplicate. Note that scales of the y axes in C and D are different. (E) Effect of FX deletion in the GIRK1 promoter on LPDS stimulation of promoter activity. Cells cultured in FBS or LPDS were transfected with either the full-length GIRK1 promoter (p30) or the FX deletion mutant. The activity of the p30 promoter in FBS was considered as 1. *P < 0.05, **P < 0.001 compared with control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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