title: Probucol prevents atrial remodeling by inhibiting oxidative stress and TNF-α/NF-κB/TGF-β signal transduction pathway in alloxan-induced diabetic rabbits.
abstract: BACKGROUND
  Diabetes mellitus (DM) is an independent risk factor for atrial fibrillation (AF). However, the underlying mechanisms for the increased propensity for AF in the setting of DM and the potential effects of probucol on atrial remodeling remain unclear.
  
  
  RESULTS
  Eighty Japanese rabbits were randomly assigned to normal/control group (Control, n = 20), alloxan-induced diabetic group (DM, n = 20), probucol-treated group (Control-P, n = 20), and probucol-treated diabetic group (DM-P, n = 20). Rabbits in the DPR and CPR groups were orally administered probucol (1,000 mg/day) for 8 weeks. Serum and left atrial tissue malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), and catalase (CAT) levels were assessed. Isolated Langendorff perfused rabbit hearts were prepared to evaluate atrial refractory effective period (AERP) and its dispersion (AERPD), interatrial conduction time (IACT), and vulnerability to AF. Atrial interstitial fibrosis was also evaluated. The mRNA expression levels of TNF-α and TLR4 were analyzed. The protein expressions of NF-κB, HSP70, TGF-β, and ERK in left atrial tissue were analyzed by Western blot. Probucol administration decreased the inducibility of AF in diabetic rabbits and attenuated atrial interstitial fibrosis. The DM-P rabbits exhibited significant alleviation of oxidative stress, evidenced by reduced serum and tissue MDA, compared with diabetic rabbits. Moreover, NF-κB, TGF-β, and HSP70 protein expression and TNF-α mRNA expression were significantly downregulated by probucol treatment in alloxan-induced diabetic rabbits.
  
  
  CONCLUSIONS
  Probucol prevents atrial remodeling and suppresses AF development in alloxan-induced diabetic rabbits. Its inhibitory effects on oxidative stress, NF-κB, TGF-β, and TNF-α overexpression may contribute to its antiremodeling effects.
authors.affiliation: Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Huaying
authors.initials: H
authors.lastname: Fu
authors.forename: Guangping
authors.initials: G
authors.lastname: Li
authors.forename: Changle
authors.initials: C
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Xinghua
authors.initials: X
authors.lastname: Wang
authors.forename: Lijun
authors.initials: L
authors.lastname: Cheng
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D064752:Atrial Remodeling / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005355:Fibrosis; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011341:Probucol / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D018836:Inflammation Mediators; D016328:NF-kappa B; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D011341:Probucol
keywords: atrial fibrillation; diabetes mellitus; inflammation; oxidative stress; probucol; remodeling; signal transduction pathway