CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy

PLoS One. 2013 Aug 30;8(8):e73490. doi: 10.1371/journal.pone.0073490. eCollection 2013.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve Stenosis / complications
  • Aortic Valve Stenosis / enzymology
  • Aortic Valve Stenosis / pathology
  • Aortic Valve Stenosis / physiopathology
  • Arrhythmias, Cardiac / enzymology
  • Arrhythmias, Cardiac / etiology*
  • Arrhythmias, Cardiac / physiopathology
  • Arrhythmias, Cardiac / prevention & control*
  • Biomarkers / metabolism
  • Cardiomegaly / complications*
  • Cardiomegaly / enzymology*
  • Cardiomegaly / physiopathology
  • Chronic Disease
  • Connexin 43 / metabolism
  • Cytochrome P-450 Enzyme System / metabolism*
  • Disease Susceptibility / complications
  • Disease Susceptibility / enzymology
  • Disease Susceptibility / pathology
  • Disease Susceptibility / physiopathology
  • Electrophysiological Phenomena
  • Endomyocardial Fibrosis / complications
  • Endomyocardial Fibrosis / enzymology
  • Endomyocardial Fibrosis / pathology
  • Endomyocardial Fibrosis / physiopathology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Pressure
  • Receptors, Adrenergic, beta / metabolism
  • Survival Analysis
  • Ventricular Remodeling

Substances

  • Biomarkers
  • Connexin 43
  • Receptors, Adrenergic, beta
  • Cytochrome P-450 Enzyme System
  • arachidonate epoxygenase