Parasympathetic response in chick myocytes and mouse heart is controlled by SREBP.
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, I 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 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 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 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.
Molecular Cardiology Research Institute, Department of Medicine, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Ho-Jin
HJ
Park
Serban P
SP
Georgescu
Chuang
C
Du
Christopher
C
Madias
Mark J
MJ
Aronovitz
C Michael
CM
Welzig
Bo
B
Wang
Ulrike
U
Begley
Yali
Y
Zhang
Robert O
RO
Blaustein
Richard D
RD
Patten
Richard H
RH
Karas
Herbert H
HH
Van Tol
Timothy F
TF
Osborne
Hitoshi
H
Shimano
Ronglih
R
Liao
Mark S
MS
Link
Jonas B
JB
Galper
D000109:Acetylcholine / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D006325:Heart Atria / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D017136:Ion Transport / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010275:Parasympathetic Nervous System / Q000378:metabolism* / Q000473:pathology; D011188:Potassium / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic / Q000235:genetics; D014693:Ventricular Fibrillation / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C484273:Kcnj5 protein, mouse; D008074:Lipoproteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D000109:Acetylcholine; D011188:Potassium