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

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 4

DN–SREBP-1 blocks the effect of LPDS on GIRK1 expression and IKACh.

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DN–SREBP-1 blocks the effect of LPDS on GIRK1 expression and IKACh. ...
(A) DN–SREBP-1 reverses the LPDS-mediated increase in GIRK1 promoter activity. Reporter assays were carried out in atrial myocytes cultured in FBS or LPDS and transfected with GIRK1-Luc plus a plasmid expressing either β-gal or SREBP-1c. Data are the mean of 4 experiments carried out in triplicate. **P < 0.01 compared with FBS; *P < 0.05 compared with LPDS. (B) DN–SREBP-1 blocks the LPDS-mediated increase in GIRK1 protein levels, while having no effect on GIRK1 expression in cells cultured in FBS. Embryonic chick atrial myocytes were infected with an adenoviral vector expressing GFP plus DN–SREBP-1 or GFP plus β-gal at the time of plating (MOI of 20) as described in Methods. On the third culture day, cells were harvested and expression of GIRK1 determined by Western blot analysis. Fluorescence microscopy demonstrated that 80%–90% of cells were GFP positive. (C) Densitometry scanning of 4 experiments similar to that in B. Data are normalized to the expression of Gβ. **P < 0.01 compared with FBS; *P < 0.05 compared with LPDS. (D) Effect of DN–SREBP-1 on IKACh in cells cultured in LPDS. Embryonic atrial myocytes were cultured in LPDS cells infected with adenovirus expressing GFP plus DN–SREBP-1 or β-gal. IKACh was determined as described in Figure 1A and the I-V relationship plotted. Points are the mean of 7 determinations in 3 independent cultures. The decrease in current density was significant; P < 0.03.