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Valsartan Upregulates Kir2.1 in Rats Suffering from Myocardial Infarction via Casein Kinase 2.

Li X, Hu H, Wang Y, Xue M, Li X, Cheng W, Xuan Y, Yin J, Yang N, Yan S - Cardiovasc Drugs Ther (2015)

Bottom Line: 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.AT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Shandong University, Ji'nan, Shandong, China.

ABSTRACT

Purpose: Myocardial 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.

Methods: Wistar 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.

Results: CK2 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.

Conclusions: AT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.

No MeSH data available.


Related in: MedlinePlus

Valsartan inhibited CK2 and protected KCNJ2/Kir2.1. a qPCR and immunoblots depicting the effect of valsartan on both CK2 and Kir2.1 in infarcted border and noninfarcted LVFW in MI rats. Both the upregulation of CK2 and the downregulation of Kir2.1 following MI were reversed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. MI; n = 10/group. b qPCR and immunoblots depicting the effect on CK2 in H9c2 cells. The upregulation of CK2 by hypoxia induced by CoCl2 was depressed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; n = 10/group. c qPCR and immunoblots depicting the effect on Kir2.1. The downregulation of Kir2.1 by hypoxia was improved by valsartan. Additionally, the over-expression of CK2 in the cells treated with valsartan abrogated this effect. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; #P < 0.05 vs. CoCl2 + valsartan; n = 10/group. d Autoradiograms and the EMSA quantification of Sp1 DNA-binding activity in rat hearts. The data are the fold values of DNA-binding activity in the MI+valsartan group compared with the MI group. *P < 0.05 vs. control; †P < 0.05 vs. CK2; n = 10/group. Values are means ± SDs
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Fig4: Valsartan inhibited CK2 and protected KCNJ2/Kir2.1. a qPCR and immunoblots depicting the effect of valsartan on both CK2 and Kir2.1 in infarcted border and noninfarcted LVFW in MI rats. Both the upregulation of CK2 and the downregulation of Kir2.1 following MI were reversed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. MI; n = 10/group. b qPCR and immunoblots depicting the effect on CK2 in H9c2 cells. The upregulation of CK2 by hypoxia induced by CoCl2 was depressed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; n = 10/group. c qPCR and immunoblots depicting the effect on Kir2.1. The downregulation of Kir2.1 by hypoxia was improved by valsartan. Additionally, the over-expression of CK2 in the cells treated with valsartan abrogated this effect. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; #P < 0.05 vs. CoCl2 + valsartan; n = 10/group. d Autoradiograms and the EMSA quantification of Sp1 DNA-binding activity in rat hearts. The data are the fold values of DNA-binding activity in the MI+valsartan group compared with the MI group. *P < 0.05 vs. control; †P < 0.05 vs. CK2; n = 10/group. Values are means ± SDs

Mentions: To determine whether valsartan treatment inhibited electrical remodeling following MI, we tested the expression of CK2 and KCNJ2/Kir2.1. In vivo, the upregulation of CK2 and the downregulation of KCNJ2/Kir2.1 following MI were reversed by valsartan, indicating that valsartan inhibited CK2 to reduce Kir2.1 remodeling following MI (Fig. 4a). In vitro, hypoxia increased CK2 expression, and valsartan reduces the increased CK2 expression induced by CoCl2 (Fig. 4b). The over-expression of CK2 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1 (Fig. 4c). Additionally, as the EMSA results indicate, valsartan eliminated the phosphorylation effect of CK2 on Sp1, resulting in a higher KCNJ2 expression level than in the CK2 group (Fig. 4d).Fig. 4


Valsartan Upregulates Kir2.1 in Rats Suffering from Myocardial Infarction via Casein Kinase 2.

Li X, Hu H, Wang Y, Xue M, Li X, Cheng W, Xuan Y, Yin J, Yang N, Yan S - Cardiovasc Drugs Ther (2015)

Valsartan inhibited CK2 and protected KCNJ2/Kir2.1. a qPCR and immunoblots depicting the effect of valsartan on both CK2 and Kir2.1 in infarcted border and noninfarcted LVFW in MI rats. Both the upregulation of CK2 and the downregulation of Kir2.1 following MI were reversed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. MI; n = 10/group. b qPCR and immunoblots depicting the effect on CK2 in H9c2 cells. The upregulation of CK2 by hypoxia induced by CoCl2 was depressed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; n = 10/group. c qPCR and immunoblots depicting the effect on Kir2.1. The downregulation of Kir2.1 by hypoxia was improved by valsartan. Additionally, the over-expression of CK2 in the cells treated with valsartan abrogated this effect. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; #P < 0.05 vs. CoCl2 + valsartan; n = 10/group. d Autoradiograms and the EMSA quantification of Sp1 DNA-binding activity in rat hearts. The data are the fold values of DNA-binding activity in the MI+valsartan group compared with the MI group. *P < 0.05 vs. control; †P < 0.05 vs. CK2; n = 10/group. Values are means ± SDs
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Fig4: Valsartan inhibited CK2 and protected KCNJ2/Kir2.1. a qPCR and immunoblots depicting the effect of valsartan on both CK2 and Kir2.1 in infarcted border and noninfarcted LVFW in MI rats. Both the upregulation of CK2 and the downregulation of Kir2.1 following MI were reversed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. MI; n = 10/group. b qPCR and immunoblots depicting the effect on CK2 in H9c2 cells. The upregulation of CK2 by hypoxia induced by CoCl2 was depressed by valsartan. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; n = 10/group. c qPCR and immunoblots depicting the effect on Kir2.1. The downregulation of Kir2.1 by hypoxia was improved by valsartan. Additionally, the over-expression of CK2 in the cells treated with valsartan abrogated this effect. *P < 0.05 vs. control; †P < 0.05 vs. CoCl2; #P < 0.05 vs. CoCl2 + valsartan; n = 10/group. d Autoradiograms and the EMSA quantification of Sp1 DNA-binding activity in rat hearts. The data are the fold values of DNA-binding activity in the MI+valsartan group compared with the MI group. *P < 0.05 vs. control; †P < 0.05 vs. CK2; n = 10/group. Values are means ± SDs
Mentions: To determine whether valsartan treatment inhibited electrical remodeling following MI, we tested the expression of CK2 and KCNJ2/Kir2.1. In vivo, the upregulation of CK2 and the downregulation of KCNJ2/Kir2.1 following MI were reversed by valsartan, indicating that valsartan inhibited CK2 to reduce Kir2.1 remodeling following MI (Fig. 4a). In vitro, hypoxia increased CK2 expression, and valsartan reduces the increased CK2 expression induced by CoCl2 (Fig. 4b). The over-expression of CK2 in cells treated with valsartan abrogated its beneficial effect on KCNJ2/Kir2.1 (Fig. 4c). Additionally, as the EMSA results indicate, valsartan eliminated the phosphorylation effect of CK2 on Sp1, resulting in a higher KCNJ2 expression level than in the CK2 group (Fig. 4d).Fig. 4

Bottom Line: 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.AT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.

View Article: PubMed Central - PubMed

Affiliation: School of Medicine, Shandong University, Ji'nan, Shandong, China.

ABSTRACT

Purpose: Myocardial 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.

Methods: Wistar 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.

Results: CK2 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.

Conclusions: AT1 receptor antagonist valsartan reduces CK2 activation, increases Kir2.1 expression and thereby ameliorates IK1 remodeling after MI in the rat model.

No MeSH data available.


Related in: MedlinePlus