title: Celastrol-Induced Suppression of the MiR-21/ERK Signalling Pathway Attenuates Cardiac Fibrosis and Dysfunction.
abstract: Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms.
  
  
  METHODS
  Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC) in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming growth factor beta 1 (TGF-β1), extracellular signal regulated kinases 1/2 (ERK1/2) signalling were measured using Western blotting, while the expression of miR-21was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac fibroblasts (CFs) were treated with TGF-β1 and transfected with microRNA-21(miR21).
  
  
  RESULTS
  Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP), beta-myosin heavy chain (β-MHC), miR-21 and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-21/ERK signalling pathway. Celastrol attenuated miR-21 up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-21.
  
  
  CONCLUSIONS
  MiR-21/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-21/ERK signaling pathways in vitro and in vivo.
authors.forename: Mian
authors.initials: M
authors.lastname: Cheng
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Yue
authors.initials: Y
authors.lastname: Song
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Ling
authors.initials: L
authors.lastname: Tu
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.forename: Cuntai
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D005355:Fibrosis; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000473:pathology*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000199:Actins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D053978:Pentacyclic Triterpenes; D053773:Transforming Growth Factor beta1; D014315:Triterpenes; C544013:alpha-smooth muscle actin, mouse; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D003094:Collagen; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C050414:celastrol