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 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.

Ophiopogonin D maintains Ca2+ homeostasis in rat cardiomyocytes in vitro by upregulating CYP2J3/EETs and suppressing ER stress

“…The data show that the addition of BAPTA inhibited the ER stress response and stress-mediated apoptosis in Ang II-treated car- EET biosynthesis and heart disease development. CYP2J3 overexpression prevented the formation of arrhythmogenic substrates by maintaining gap junction integrity and reducing the development of atrial fibrosis in cardiac hypertrophy [16] . The upregulation of CYP2J3/11,12-EETs during ischemic post-conditioning (HPost) induced cardioprotection by inhibiting apoptosis via the mitochondrial pathway [18] .…”

“…Accumulating evidence suggests that EETs have crucial and diverse protective roles within the cardiovascular system. Specifically, EETs have been reported to possess antiarrhythmic [16] , anti-inflammatory [17] , anti-apoptotic [18] , and antioxidant [19] functions. Additionally, CYP2J3 overexpression and increased levels of EETs have been reported to decrease ER stress signaling and ER stress-mediated apoptosis in rats with heart failure by maintaining SERCA2a activity and intracellular Ca 2+ homeostasis [20] .…”

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

“…Moreover, the circulating epoxy-metabolites that are predominantly esterifi ed with lipoprotein lipids may themselves become biologically active in other tissues after being released by lipoprotein lipases ( 81 ). There is increasing evidence for a cardioprotective role of CYP-epoxygenase metabolites from studies in animal models of ischemia/reperfusion injury, maladaptive cardiac hypertrophy, and arrhythmia ( 12,24,82 ). We showed that 17,18-EEQ and 19,20-EDP are potential candidates for mediating the antiarrhythmic effect of n-3 PUFAs ( 22 ).…”

Orally Active Epoxyeicosatrienoic Acid Analogs

“…In mice, inhibition of sEH increases endogenous EETs, improves pressure overload heart failure and reduces the incidence of arrhythmias (67). Similarly, cardiac overexpression of CYP2J2 reduces mortality and arrhythmias in transverse aortic constriction and isoproterenol infusion models of heart failure compared to wild type mice (68). Angiotensin-induced cardiac fibrosis, inflammation and hypertrophy are also reduced in CYP2J2 mice (69, 70).…”