title: Rosuvastatin suppresses atrial tachycardia-induced cellular remodeling via Akt/Nrf2/heme oxygenase-1 pathway.
abstract: Atrial fibrillation (AF) is associated with structural remodeling in atrial myocytes. Emerging evidence suggests that statin has a protective effect on AF through cholesterol-independent mechanisms. The aim of this study is to investigate whether heme oxygenase-1 (HO-1), a potent antioxidant system, mediates the suppressive effect of statin on atrial tachycardia-induced structural remodeling. Treatment of cultured atrium-derived myocytes (HL-1 cell line) with rosuvastatin enhanced HO-1 expression/activity and attenuated tachypacing-induced oxidative stress and myofibril degradation. Heme oxygenase-1 inhibitors and small-interfering RNA for HO-1 blocked the inhibitory effect of rosuvastatin on tachypacing-stimulated changes, suggesting the crucial role of HO-1 in mediating the effect of rosuvastatin. Time-dependent experiments and loss-of-function study demonstrated that Akt/Nrf2 pathways lay to the up-stream of HO-1 in this signaling cascade. Furthermore, the involvement of Akt/Nrf2/HO-1 pathway in the antioxidant effect of rosuvastatin was documented in an ex vivo tachypacing model. The suppressive effect of statin on atrial tachypacing-induced cellular remodeling is mediated via the activation of Akt/Nrf2/HO-1 signaling, which provides a possible explanation for the protective effect of statin on AF.
authors.affiliation: Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Chang-Gung University, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Yeh
authors.affiliation: Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Chang-Gung University, Taiwan.
authors.forename: Chi-Tai
authors.initials: CT
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang-Gung University College of Medicine, Chang-Gung University, Taiwan.
authors.forename: Gwo-Jyh
authors.initials: GJ
authors.lastname: Chang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, National Yang-Ming University College of Medicine, Taiwan.
authors.forename: Ying-Hwa
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Respiratory Therapy, Chang-Gung University College of Medicine, Chang-Gung University, Taiwan.
authors.forename: Ying-Ju
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Department of Biomedical Sciences, Chang-Gung University College of Medicine, Chang-Gung University, Taiwan.
authors.forename: Mei-Ling
authors.initials: ML
authors.lastname: Cheng
authors.affiliation: Cardiovascular Division, Chang-Gung Memorial Hospital, Chang-Gung University College of Medicine, Chang-Gung University, Taiwan. Electronic address: wjchen@adm.cgmh.org.tw.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D064752:Atrial Remodeling / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D000068718:Rosuvastatin Calcium / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013612:Tachycardia, Ectopic Atrial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051267:NF-E2-Related Factor 2; D000068718:Rosuvastatin Calcium; D003094:Collagen; D051547:Heme Oxygenase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Atrial fibrillation; Heme oxygenase-1; Myofibril degradation; Statin