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CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy

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Item Type:Article
Title:CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy
Creators Name:Westphal, C. and Spallek, B. and Konkel, A. and Marko, L. and Qadri, F. and Degraff, L.M. and Schubert, C. and Bradbury, J.A. and Regitz-Zagrosek, V. and Falck, J.R. and Zeldin, D.C. and Müller, D.N. and Schunck, W.H. and Fischer, R.
Abstract:Maladaptive cardiac hypertrophy predisposes one to arrhythmia and sudden death. Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) promote anti-inflammatory and antiapoptotic mechanisms, and are involved in the regulation of cardiac Ca(2+)-, K(+)- and Na(+)-channels. To test the hypothesis that enhanced cardiac EET biosynthesis counteracts hypertrophy-induced electrical remodeling, male transgenic mice with cardiomyocyte-specific overexpression of the human epoxygenase CYP2J2 (CYP2J2-TG) and wildtype littermates (WT) were subjected to chronic pressure overload (transverse aortic constriction, TAC) or {beta}-adrenergic stimulation (isoproterenol infusion, ISO). TAC caused progressive mortality that was higher in WT (42% over 8 weeks after TAC), compared to CYP2J2-TG mice (6%). In vivo electrophysiological studies, 4 weeks after TAC, revealed high ventricular tachyarrhythmia inducibility in WT (47% of the stimulation protocols), but not in CYP2J2-TG mice (0%). CYP2J2 overexpression also enhanced ventricular refractoriness and protected against TAC-induced QRS prolongation and delocalization of left ventricular connexin-43. ISO for 14 days induced high vulnerability for atrial fibrillation in WT mice (54%) that was reduced in CYP-TG mice (17%). CYP2J2 overexpression also protected against ISO-induced reduction of atrial refractoriness and development of atrial fibrosis. In contrast to these profound effects on electrical remodeling, CYP2J2 overexpression only moderately reduced TAC-induced cardiac hypertrophy and did not affect the hypertrophic response to {beta}-adrenergic stimulation. These results demonstrate that enhanced cardiac EET biosynthesis protects against electrical remodeling, ventricular tachyarrhythmia, and atrial fibrillation susceptibility during maladaptive cardiac hypertrophy.
Keywords:Aortic Valve Stenosis, Cardiac Arrhythmias, Biological Markers, Cardiomegaly, Chronic Disease, Connexin 43, Cytochrome P-450 Enzyme System, Disease Susceptibility, Electrophysiological Phenomena, Endomyocardial Fibrosis, Pressure, Beta Adrenergic Receptors, Survival Analysis, Ventricular Remodeling, Animals, Mice
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:8
Number:8
Page Range:e73490
Date:30 August 2013
Official Publication:https://doi.org/10.1371/journal.pone.0073490
PubMed:View item in PubMed

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