Abstract
Congestive heart failure (CHF) is associated with susceptibility to lethal arrhythmias and typically increases levels of tumor necrosis factor-alpha (TNF-alpha) and its receptor, TNFR1. CHF down-regulates rapid delayed-rectifier K(+) current (I(Kr)) and delays cardiac repolarization. We studied the effects of TNF-alpha on cloned HERG K(+) channel (human ether-a-go-go-related gene) in HEK293 cells and native I(Kr) in canine cardiomyocytes with whole-cell patch clamp techniques. TNF-alpha consistently and reversibly decreased HERG current (I(HERG)). Effects of TNF-alpha were concentration-dependent, increased with longer incubation period, and occurred at clinically relevant concentrations. TNF-alpha had similar inhibitory effects on I(Kr) and markedly prolonged action potential duration (APD) in canine cardiomyocytes. Immunoblotting analysis demonstrated that HERG protein level was slightly higher in canine hearts with tachypacing-induced CHF than in healthy hearts, and TNF-alpha slightly increased HERG protein level in CHF but not in healthy hearts. In cells pretreated with the inhibitory anti-TNFR1 antibody, TNF-alpha lost its ability to suppress I(HERG), indicating a requirement of TNFR1 activation for HERG suppression. Vitamin E or MnTBAP (Mn(III) tetrakis(4-benzoic acid) porphyrin chloride), a superoxide dismutase mimic) prevented, whereas the superoxide anion generating system xanthine/xanthine oxidase mimicked, TNF-alpha-induced I(HERG) depression. TNF-alpha caused robust increases in intracellular reactive oxygen species, and vitamin E and MnTBAP abolished the increases, in both HEK293 cells and canine ventricular myocytes. We conclude that the TNF-alpha/TNFR1 system impairs HERG/I(Kr) function mainly by stimulating reactive oxygen species, particularly superoxide anion, but not by altering HERG expression; the effect may contribute to APD prolongation by TNF-alpha and may be a novel mechanism for electrophysiological abnormalities and sudden death in CHF.
Highlights
From the ‡Research Center, Montreal Heart Institute, Montreal, Quebec H1T 1C8, the §Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, and the §§Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3A 2T5, Canada
We studied the effects of TNF-␣ on cloned human ether-a-go-go-related gene (HERG) K؉ channel in HEK293 cells and native IKr in canine cardiomyocytes with whole-cell patch clamp techniques
We conclude that the TNF-␣/TNFR1 system impairs HERG/IKr function mainly by stimulating reactive oxygen species, superoxide anion, but not by altering HERG expression; the effect may contribute to action potential duration (APD) prolongation by TNF-␣ and may be a novel mechanism for electrophysiological abnormalities and sudden death in CHF
Summary
Received for publication, January 16, 2004, and in revised form, February 6, 2004. Jingxiong Wang‡§¶ʈ, Huizhen Wang‡¶, Yiqiang Zhang‡§**, Huanhuan Gao‡ ‡‡, Stanley Nattel‡§ §§, and Zhiguo Wang‡§¶¶. TNF-␣ had similar inhibitory effects on IKr and markedly prolonged action potential duration (APD) in canine cardiomyocytes. We conclude that the TNF-␣/TNFR1 system impairs HERG/IKr function mainly by stimulating reactive oxygen species, superoxide anion, but not by altering HERG expression; the effect may contribute to APD prolongation by TNF-␣ and may be a novel mechanism for electrophysiological abnormalities and sudden death in CHF. A recent study demonstrated that transgenic mice overexpressing TNF-␣ with heart failure had significantly prolonged APD [9]. It is unknown whether TNF-␣ affects cardiac Kϩ channels. We examined the hypothesis that TNF-␣ might affect HERG/IKr, thereby potentially contributing to CHF-related repolarization abnormalities
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