GW24-e3518 Probucol prevents atrial remodeling by inhibiting reactive oxygen species production and NF-kappaB activation in alloxan-induced diabetic rabbits

Objectives This study sought to assess the effects of probucol on atrial remodelling and atrial fibrillation (AF) promotion in alloxan-induced diabetic rabbits and to elucidate the underlying mechanisms. Methods 40 Japanese rabbits were randomly assigned to a normal control group (C, n = 10), alloxan-induced diabetic group (DM, n = 10), a and probucol-treated diabetic group (DPR, probucol-treated group (CPR, n = 10) n = 10). Rabbits in the DPR and CPR groups were orally administered Probucol (1000mg/day) for 8 weeks. Plasma malonaldehyde (MDA) levels were measured. The protein expression of nuclear factor κB (NF-κB) and transforming growth factor-β(TGF-β) in left atrial tissue were analysed by western blot, the mRNA expression levels of tumour necrosisfactor-α(TNF-α) were analysed by RT-PCR methods. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period dispersion (AERPD), interatrial conduction time (IACT) and vulnerability to AF. Atrial interstitial fibrosis was evaluated by Sirius-Red staining. Results The DPR rabbits exhibited significant alleviation of oxidative stress displayed as decreased plasma MDA. Probucol administration increases stability of vulnerable atrial fibrillation compared with diabetic rabbits (P < 0.05). Probucol significantly downregulated atrial NF-κB, TGF-β protein expression and TNF-α mRNA expression in atrial tissue of DPR rabbits. Histological analysis revealed suppression of DM-related histological changes (interstitial fibrosis) by probucol. Conclusions Probucol attenuated atrial remodelling and prevented AF development in alloxan-induced diabetic rabbits. Its inhibition on reactive oxygen species production, NF-κB, TGF-β and TNF-α overexpression may contribute to its anti-remodelling effects.