Following myocardial infarction, SREBP-1 knockout mice were significantly more likely to develop inducible ventricular tachycardia compared to wild-type mice (89% vs 43%, P<0.05).
SREBP-1 regulates the cardiac parasympathetic response via GIRK1 expression, and its absence increases susceptibility to ventricular arrhythmias following myocardial infarction in mice.
Absolute Event Rate: 89% vs 43%
p-value: p=<0.05
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.
Park et al. (Wed,) conducted a other in Ventricular arrhythmia post-myocardial infarction (n=16). SREBP-1 knockout vs. Wild-type was evaluated on Inducible ventricular tachycardia (p=<0.05). Following myocardial infarction, SREBP-1 knockout mice were significantly more likely to develop inducible ventricular tachycardia compared to wild-type mice (89% vs 43%, P<0.05).