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 5

Response of the heart to parasympathetic stimulation and the expression of GIRK1 in SREBP-1 KO mice.

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Response of the heart to parasympathetic stimulation and the expression ...
(A) Comparison of the negative chronotropic response of WT and SREBP-1 KO mice to carbamylcholine. Continuous ECGs were recorded as described in Methods. Mice were treated with an intraperitoneal injection of propranolol, 1 mg/kg, and 20 minutes later by intraperitoneal injection of carbachol, 0.2 mg/kg. Data represent the mean heart rate of 7 age-matched mice. (B) Quantitation of the negative chronotropic response to carbachol in WT and SREBP-1 KO mice. The plateau time of bradycardia and the time elapsed for 80% (Rec80) recovery to baseline heart rate, defined as heart rate following propranolol treatment, were determined as described in Methods. *P < 0.05; †P < 0.05. (C) Expression of SREBP-1 and GIRK1 in atria of WT and SREBP-1 KO mice. Atria of age-matched male WT and SREBP-1 KO mice were harvested and homogenized, and SREBP-1 (left panel) and GIRK1 (right panel) were determined by Western blot analysis. (D) Mean intensity of both glycosylated and unglycosylated GIRK1 bands determined by densitometry analysis of autoradiographs from 8 WT and 8 SREBP-1 KO mice normalized to the expression of Gβ; **P < 0.03.