This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 98/8/1040    most recent 01.RES.0000218989.52072.e7v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, C. Articles by Levitan, E. S. Search for Related Content PubMed PubMed Citation Articles by Zhou, C. Articles by Levitan, E. S. Related Collections ACE/Angiotension receptors Arrythmias-basic studies Cell signalling/signal transduction Ion channels/membrane transport Physiological and pathological control of gene expression

(Circulation Research. 2006;98:1040.)
© 2006 American Heart Association, Inc.

Cellular Biology

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, 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.

Correspondence to Dr Edwin Levitan, University of Pittsburgh, E1351 Biomedical Science Tower, Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15261. 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 (I_to) 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

This article has been cited by other articles:

				D. R. Van Wagoner Evaluating the impact of atrial dilatation on atrial calcium cycling Eur. Heart J., May 1, 2008; 29(9): 1084 - 1085. [Full Text] [PDF]

				S. Dinanian, C. Boixel, C. Juin, J.-S. Hulot, A. Coulombe, C. Rucker-Martin, N. Bonnet, B. Le Grand, M. Slama, J.-J. Mercadier, et al. Downregulation of the calcium current in human right atrial myocytes from patients in sinus rhythm but with a high risk of atrial fibrillation Eur. Heart J., May 1, 2008; 29(9): 1190 - 1197. [Abstract] [Full Text] [PDF]

				P. M. Sonner, J. A. Filosa, and J. E. Stern Diminished A-type potassium current and altered firing properties in presympathetic PVN neurones in renovascular hypertensive rats J. Physiol., March 15, 2008; 586(6): 1605 - 1622. [Abstract] [Full Text] [PDF]

				I. Murtaza, H.-X. Wang, X. Feng, N. Alenina, M. Bader, B. S. Prabhakar, and P.-F. Li Down-regulation of Catalase and Oxidative Modification of Protein Kinase CK2 Lead to the Failure of Apoptosis Repressor with Caspase Recruitment Domain to Inhibit Cardiomyocyte Hypertrophy J. Biol. Chem., March 7, 2008; 283(10): 5996 - 6004. [Abstract] [Full Text] [PDF]

				Z. Ren, F. J. Raucci Jr., D. M. Browe, and C. M. Baumgarten Regulation of swelling-activated Cl- current by angiotensin II signalling and NADPH oxidase in rabbit ventricle Cardiovasc Res, January 1, 2008; 77(1): 73 - 80. [Abstract] [Full Text] [PDF]

				H. E. Cingolani and I. L. Ennis Sodium-Hydrogen Exchanger, Cardiac Overload, and Myocardial Hypertrophy Circulation, March 6, 2007; 115(9): 1090 - 1100. [Full Text] [PDF]

				Y. Liu, W. Hao, M. Letiembre, S. Walter, M. Kulanga, H. Neumann, and K. Fassbender Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis: Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species J. Neurosci., December 13, 2006; 26(50): 12904 - 12913. [Abstract] [Full Text] [PDF]