Abstract-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 3Ј untranslated region (3Ј UTR) of the Kv4.3 channel transcript confers Ang II sensitivity to a promoter-reporter construct. In contrast, Kv4.2 and Kv1.5 3Ј-UTR sequences are insensitive to Ang II. Both Kv4.3 3Ј-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 (AT 1 ) receptors and abolished by NADPH oxidase inhibitors and dominant negative rac. The Ang II effect is also blocked by expression of superoxide dismutase (SOD) Key Words: potassium channel Ⅲ angiotensin Ⅲ stretch Ⅲ NADPH oxidase Ⅲ ROS Ⅲ mRNA stability C ardiac hypertrophy, caused by congestive heart failure, hypertension, and pregnancy, is associated with a decrease in the transient outward current (I to ) in ventricular cardiac myocytes. 1,2 The suppression of ventricular I to is thought to promote calcium influx and myocyte contraction in the early adaptive phase of hypertrophy but may eventually induce calcium overloading of the sarcoplasmic reticulum, leading to arrhythmic firing and sudden death. 3,4 The reduction of I to is likely related to the downregulation of Kv4.3 mRNA and protein that occurs with congestive heart failure in humans and hypertension in animals. 5,6 The finding that the latter effect is blocked by angiotensin converting enzyme (ACE) inhibition implicated angiotensin II (Ang II) in the control of cardiac Kv4.3 gene expression. 7 Follow-up experiments have shown that Ang II acts directly on cultured neonatal rat ventricular myocytes via Ang II type 1 (AT 1 ) receptors to decrease Kv4.3 mRNA and protein. 8 However, the onset of the effect was more rapid than the turnover of the channel mRNA, and Ang II did not act on the Kv4.3 promoter. 8 This indirect evidence led to the proposal that Ang II destabilizes Kv4.3 mRNA in cardiac myocytes. In contrast, the ␣ 1 -adrenergic receptor agonist phenylephrine downregulated Kv4.3 promoter activity, 8 suggesting that G q -mediated signaling shared by AT 1 receptors and ␣ 1 -adrenergic receptors might not be involved in this Ang II effect on mRNA stability.,It has been recently demonstrated that AT 1 receptors can act via the small G protein rac to stimulate NADPH oxidase in cardiac myocytes. 9,10 NADPH oxidase produces superoxide, which serves as a physiological reactive oxygen species (ROS) messenger within the cell. Separate studies have also shown that AT 1 receptors, rac and ROS production are activated by mechanical stretch of cardiac myocytes. 11-13 Thus, we hypothesized that Ang II and stretch can act via the AT 1 receptor-NADPH oxidase pathway to regulate cardiac myocyte Kv4.3 mRNA stability. Here...