ABSTRACT
AIM:
To investigate the
regulation mechanism for insufficient KChIP 2 expression induces Ito,f
downregulation and arrhythmogene-sis in
cardiac hypertrophy .
METHODS:
Bidirectional manipulations of MG 53 expression were performed by adenoviral overexpression of MG53 or knockdown of MG53 with
RNA interference in neonatal
rat ventricular
myocytes with or without PE stimulation .Ito,f was re-corded with patch clamp in whole-
cell mode 48 h after adenoviral
transfection .Then the WT or MG53 knockout ( MG53 -/-)
mouse model of
left ventricular hypertrophy induced by transverse aortic
constriction ( TAC) were used to detect the susceptibility to ventricu-lar
arrhythmia.
RESULTS:
Here, we show
muscle-specific MG53 regulates KChIP2 expression and Ito,f densities, where they are downregulated in
hearts from MG53
knockout mice and MG53 knockdown
rat cardiomyocytes , but upregulated in MG53 overexpressed
cells.MG53 expression is decreased in
phenylephrine ( PE)-induced
cardiomyocyte hypertrophy and restoration of MG 53 rescues PE-induced
downregulation of KChIP2 and Ito,f.Furthermore, MG53 is decreased in a
mouse model of
hypertrophy induced by transverse aortic
constriction and ablation of MG 53 increases the susceptibility to ventricular
arrhythmia by exaggerating Ito,f
remodeling.CON-CLUSIONThese findings establish MG53 as a novel regulator of Ito,f and its central
role in arrhythmogenesis in
hypertrophy .