Abstract
PurposeMyocardial infarction (MI) results in an increased susceptibility to ventricular arrhythmias, due in part to decreased inward-rectifier K+ current (IK1), which is mediated primarily by the Kir2.1 protein. The use of renin-angiotensin-aldosterone system antagonists is associated with a reduced incidence of ventricular arrhythmias. Casein kinase 2 (CK2) binds and phosphorylates SP1, a transcription factor of KCNJ2 that encodes Kir2.1. Whether valsartan represses CK2 activation to ameliorate IK1 remodeling following MI remains unclear.MethodsWistar rats suffering from MI received either valsartan or saline for 7 days. The protein levels of CK2 and Kir2.1 were each detected via a Western blot analysis. The mRNA levels of CK2 and Kir2.1 were each examined via quantitative real-time PCR.ResultsCK2 expression was higher at the infarct border; and was accompanied by a depressed IK1/Kir2.1 protein level. Additionally, CK2 overexpression suppressed KCNJ2/Kir2.1 expression. By contrast, CK2 inhibition enhanced KCNJ2/Kir2.1 expression, establishing that CK2 regulates KCNJ2 expression. Among the rats suffering from MI, valsartan reduced CK2 expression and increased Kir2.1 expression compared with the rats that received saline treatment. In vitro, hypoxia increased CK2 expression and valsartan inhibited CK2 expression. The over-expression of CK2 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1.ConclusionsAT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.
Highlights
Ventricular arrhythmias following myocardial infarction (MI) remain a major cause of mortality [1]
In an effort to determine the role of Casein kinase 2 (CK2) in acute myocardial infarction (AMI), we found that CK2 was significantly upregulated
The cells transfected with CK2 had a lower IK1 density than the control cells, and the difference was eliminated by adding TBB or valsartan (Fig. 3b)
Summary
Ventricular arrhythmias following myocardial infarction (MI) remain a major cause of mortality [1]. Numerous studies have confirmed that decreased inward-rectifier K+ current (IK1), along with the decreased expression of KCNJ2 mRNA and its encoded Kir2.1 protein, is a prominent feature of ventricular electrical remodeling following MI [2,3,4]. The gene regulation of these pathways is poorly understood. Recent studies have discovered that CK2 is associated with several diseases, such as cardiac hypertrophy [6], and is involved in ion channel regulation [7, 8]. Several studies have demonstrated that CK2 binds to and induces the phosphorylation of transcription factor SP1 serine, resulting in the suppression of gene expression [9, 10]. SP1 is an important transcription factor for KCNJ2 [11]
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