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Circulation Research. 2006
Published online before print March 23, 2006, doi: 10.1161/01.RES.0000218989.52072.e7
A more recent version of this article appeared on April 28, 2006
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Submitted on October 12, 2005
Revised on March 7, 2006
Accepted on March 14, 2006

Angiotensin II and Stretch Activate NADPH Oxidase to Destabilize Cardiac Kv4.3 Channel mRNA

Chaoming Zhou ; Chandra Ziegler ; Lori A. Birder ; Alexandre F. R. Stewart ; and Edwin S. Levitan *

From the Departments of Pharmacology (C. Zhou, C. Ziegler, E.S.L.) and Medicine (L.A.B.), University of Pittsburgh, Pa; and University of Ottawa Heart Institute (A.F.R.S.), Ontario, Canada.

* To whom correspondence should be addressed. E-mail: Levitan{at}server.pharm.pitt.edu.

Pathological and physiological hypertrophy of the heart is associated with decreased expression of the Kv4.3 transient outward current (Ito) channel. The downregulation of channel mRNA and protein, which may be proarrhythmic, is recapitulated with cultured neonatal rat ventricular myocytes treated with angiotensin II (Ang II). Here we show that the 4.9 kb 3' untranslated region (3' UTR) of the Kv4.3 channel transcript confers Ang II sensitivity to a promoter-reporter construct. In contrast, Kv4.2 and Kv1.5 3'-UTR sequences are insensitive to Ang II. Both Kv4.3 3'-UTR reporter mRNA and activity are decreased in Ang II-treated cardiac myocytes, in accordance with a decrease in mRNA stability. This regulation is mediated by Ang II type 1 (AT1) receptors and abolished by NADPH oxidase inhibitors and dominant negative rac. The Ang II effect is also blocked by expression of superoxide dismutase (SOD), but not catalase, showing that superoxide is required. Dominant negative subunits, enzyme inhibitors and hydrogen peroxide experiments show that the apoptosis signal-regulating kinase 1 (ASK1)-p38 kinase pathway mediates downstream signaling from NADPH oxidase. Mechanical stretch also downregulates Kv4.3 3'-UTR reporter activity and this requires AT1 receptors and NADPH oxidase. Thus, activation of AT1 receptors by Ang II or stretch specifically destabilizes cardiac myocyte Kv4.3 channel mRNA by activating NADPH oxidase. These results link long-term control of cardiac K+ channel gene expression to a physiological reactive oxygen species signaling pathway.
Key words: potassium channel • angiotensin • stretch • NADPH oxidase • ROS • mRNA stability




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