학술논문
Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP
Document Type
Academic Journal
Author
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.
Source
Journal of Clinical Investigation. Jan, 2008, Vol. 118 Issue 1, p259, 13 p.
Subject
Language
English
ISSN
0021-9738
Abstract
Parasympathetic stimulation of the heart, which provides protection from arrhythmias and sudden death, involves activation of the G protein--coupled inward rectifying [K.sup.+] channel GIRK1/4 and results in an acetylcholine-sensitive [K.sup.+] current, [I.sub.KACh]. 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 [I.sub.KACh] 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 [I.sub.KACh] 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. [I.sub.KACh], 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.
Introduction The balance between the response of the heart to sympathetic and parasympathetic stimuli not only determines the rate and force of contraction but also plays a role in regulating [...]
Introduction The balance between the response of the heart to sympathetic and parasympathetic stimuli not only determines the rate and force of contraction but also plays a role in regulating [...]