Independent regulation of cardiac Kv4.3 potassium channel expression by angiotensin II and phenylephrine

被引:67
作者
Zhang, TT
Takimoto, K
Stewart, AFR
Zhu, CX
Levitan, ES
机构
[1] Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Sch Med, Cardiovasc Inst, Pittsburgh, PA 15261 USA
关键词
hypertrophy; gene regulation; ion channels/membrane transport; angiotensin-converting enzyme/angiotensin receptor; physiological and pathological control of gene expression;
D O I
10.1161/01.RES.88.5.476
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Hypertrophied cardiac myocytes exhibit prolonged action potentials and decreased transient outward potassium current (I-to). Because Kv4.3 is a major contributor to I-to we studied regulation of its expression in neonatal rat cardiac myocytes in response to the known stimulators of cardiac myocyte hypertrophy, angiotensin II (Ang II) and phenylephrine (PE). RNase protection assays and immunoblots revealed that Ang II and PE each downregulate Kv4.3 mRNA and protein. However, although PE induces a faster and more extensive hypertrophic response than Ang II, the PE effect on Kv4.3 mRNA develops slowly and is sustained, whereas Ang II rapidly and transiently decreases Kv4.3 mRNA expression. Turnover measurements revealed that Kv4.3 mRNA is very stable, with a half-life >20 hours. This suggests that Ang II must destabilize the channel mRNA. In contrast, PE does not affect the rate of Kv4.3 mRNA degradation. To test for transcriptional regulation, the 5' flanking region of the rat Kv4.3 gene was cloned, and Kv4.3 promoter-reporter constructs were expressed in cardiac myocytes. Whereas Ang II was found to have no effect on transcription, PE inhibits Kv4.3 promoter activity. Pharmacological experiments also indicate that PE and Ang II act independently to downregulate Kv4.3 gene expression. Thus, regulation of Kv4.3 gene expression is not a simple secondary response to hypertrophy. Rather, Ang II and PE use different mechanisms to decrease Kv4.3 channel expression in neonatal rat cardiac myocytes.
引用
收藏
页码:476 / 482
页数:7
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