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

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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)259-271
Number of pages13
JournalJournal of Clinical Investigation
Volume118
Issue number1
DOIs
StatePublished - Jan 2 2008

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Muscle Cells
Lipids
Knockout Mice
Cardiac Arrhythmias
E-Box Elements
Response Elements
Sterols
Ventricular Tachycardia
Sudden Death
Lipid Metabolism
GTP-Binding Proteins
Lipoproteins
Acetylcholine
Homeostasis
Transcription Factors
Myocardial Infarction
Serum

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Park, H. J., Georgescu, S. P., Du, C., Madias, C., Aronovitz, M. J., Welzig, C. M., ... Galper, J. B. (2008). Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. Journal of Clinical Investigation, 118(1), 259-271. https://doi.org/10.1172/JCI32011

Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. / Park, Ho Jin; Georgescu, Serban P.; Du, Chuang; Madias, Christopher; Aronovitz, Mark J.; Welzig, C. Michael; Wang, Bo; Begley, Ulrike; Zhang, Yali; Blaustein, Robert O.; Patten, Richard D.; Karas, Richard H.; Van Tol, Herbert H.; Osborne, Timothy F.; Shimano, Hitoshi; Liao, Ronglih; Link, Mark S.; Galper, Jonas B.

In: Journal of Clinical Investigation, Vol. 118, No. 1, 02.01.2008, p. 259-271.

Research output: Contribution to journalArticle

Park, HJ, Georgescu, SP, Du, C, Madias, C, Aronovitz, MJ, Welzig, CM, Wang, B, Begley, U, Zhang, Y, Blaustein, RO, Patten, RD, Karas, RH, Van Tol, HH, Osborne, TF, Shimano, H, Liao, R, Link, MS & Galper, JB 2008, 'Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP', Journal of Clinical Investigation, vol. 118, no. 1, pp. 259-271. https://doi.org/10.1172/JCI32011
Park HJ, Georgescu SP, Du C, Madias C, Aronovitz MJ, Welzig CM et al. Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. Journal of Clinical Investigation. 2008 Jan 2;118(1):259-271. https://doi.org/10.1172/JCI32011
Park, Ho Jin ; Georgescu, Serban P. ; Du, Chuang ; Madias, Christopher ; Aronovitz, Mark J. ; Welzig, C. Michael ; Wang, Bo ; Begley, Ulrike ; Zhang, Yali ; Blaustein, Robert O. ; Patten, Richard D. ; Karas, Richard H. ; Van Tol, Herbert H. ; Osborne, Timothy F. ; Shimano, Hitoshi ; Liao, Ronglih ; Link, Mark S. ; Galper, Jonas B. / Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 1. pp. 259-271.
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AU - Welzig, C. Michael

AU - Wang, Bo

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AU - Patten, Richard D.

AU - Karas, Richard H.

AU - Van Tol, Herbert H.

AU - Osborne, Timothy F.

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