CYP2J2 Overexpression Protects against Arrhythmia Susceptibility in Cardiac Hypertrophy

Christina Westphal, Bastian Spallek, Anne Konkel, Lajos Marko, Fatimunnisa Qadri, Laura M. DeGraff, Carola Schubert, J. Alyce Bradbury, Vera Regitz-Zagrosek, John R. Falck, Darryl C. Zeldin, Dominik N. Müller, Wolf Hagen Schunck, Robert Fischer

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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 Ca2+-, 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 β-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 β-adrenergic stimulation. These results demonstrate that enhanced cardiac EET biosynthesis protects against electrical remodeling, ventricular tachyarrhythmia, and atrial fibrillation susceptibility during maladaptive cardiac hypertrophy.

Original languageEnglish (US)
Article numbere73490
JournalPLoS One
Volume8
Issue number8
DOIs
Publication statusPublished - Aug 30 2013

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ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Westphal, C., Spallek, B., Konkel, A., Marko, L., Qadri, F., DeGraff, L. M., ... Fischer, R. (2013). CYP2J2 Overexpression Protects against Arrhythmia Susceptibility in Cardiac Hypertrophy. PLoS One, 8(8), [e73490]. https://doi.org/10.1371/journal.pone.0073490