title: CYP2J2 overexpression protects against arrhythmia susceptibility in cardiac hypertrophy.
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.
authors.affiliation: Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Westphal
authors.forename: Bastian
authors.initials: B
authors.lastname: Spallek
authors.forename: Anne
authors.initials: A
authors.lastname: Konkel
authors.forename: Lajos
authors.initials: L
authors.lastname: Marko
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Carola
authors.initials: C
authors.lastname: Schubert
authors.forename: J Alyce
authors.initials: JA
authors.lastname: Bradbury
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D015415:Biomarkers / Q000378:metabolism; D006332:Cardiomegaly / Q000150:complications* / Q000201:enzymology* / Q000503:physiopathology; D002908:Chronic Disease; D018031:Connexin 43 / Q000378:metabolism; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004198:Disease Susceptibility / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D055724:Electrophysiological Phenomena; D004719:Endomyocardial Fibrosis / Q000150:complications / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011312:Pressure; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D016019:Survival Analysis; D020257:Ventricular Remodeling
chemical_list: D015415:Biomarkers; C000717350:CYP2J2 protein, human; D018031:Connexin 43; D011943:Receptors, Adrenergic, beta; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2
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