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.
Highlights
Cytochrome P450 (CYP)-dependent eicosanoids, such as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), may play crucial roles in the development of heart disease
We found that CYP2J2 overexpression mediated strong antiarrhythmic effects in both models, suggesting that EETs are involved in endogenous mechanisms preventing maladaptive electrical remodeling during cardiac hypertrophy
The survival rate during the development of pressure overloadinduced cardiac hypertrophy was significantly higher in CYP2J2TG compared to wildtype littermates (WT) mice (Fig. 1A)
Summary
Cytochrome P450 (CYP)-dependent eicosanoids, such as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), may play crucial roles in the development of heart disease. EETs exert anti-inflammatory and antiapoptotic effects in cardiomyocytes and ameliorate cardiac ischemiareperfusion injury, whereas 20-HETE causes detrimental effects in the same settings [1,2,3,4]. EETs modulate the electrophysiological properties of the heart by regulating L-type Ca2+, Na+, and ATP-sensitive K+ (KATP) channel activities [5,6,7,8,9]. EET pretreatments efficiently reduced myocardial infarction size after transient coronary artery occlusion [2,12,13]. Further studies revealed an essential role of EETs in mediating the beneficial effects of preand postconditioning [14,15,16]
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