title: Inhibition of the Unfolded Protein Response Mechanism Prevents Cardiac Fibrosis.
abstract: BACKGROUND
  Cardiac fibrosis attributed to excessive deposition of extracellular matrix proteins is a major cause of heart failure and death. Cardiac fibrosis is extremely difficult and challenging to treat in a clinical setting due to lack of understanding of molecular mechanisms leading to cardiac fibrosis and effective anti-fibrotic therapies. The objective in this study was to examine whether unfolded protein response (UPR) pathway mediates cardiac fibrosis and whether a pharmacological intervention to modulate UPR can prevent cardiac fibrosis and preserve heart function.
  
  
  RESULTS
  We demonstrate here that the mechanism leading to development of fibrosis in a mouse with increased expression of calreticulin, a model of heart failure, stems from impairment of endoplasmic reticulum (ER) homeostasis, transient activation of the unfolded protein response (UPR) pathway and stimulation of the TGFβ1/Smad2/3 signaling pathway. Remarkably, sustained pharmacologic inhibition of the UPR pathway by tauroursodeoxycholic acid (TUDCA) is sufficient to prevent cardiac fibrosis, and improved exercise tolerance.
  
  
  CONCLUSIONS
  We show that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from transient activation of UPR pathway leading to persistent remodelling of cardiac tissue. Blocking the activation of the transiently activated UPR pathway by TUDCA prevented cardiac fibrosis, and improved prognosis. These findings offer a window for additional interventions that can preserve heart function.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Jody
authors.initials: J
authors.lastname: Groenendyk
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.|School of Dietetics and Human Nutrition, McGill University, Ste. Anne de Bellevue, Quebec, H9X 3V9, Canada.
authors.forename: Dukgyu
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jung
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
authors.affiliation: Department of Pediatrics, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.|Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.affiliation: School of Dietetics and Human Nutrition, McGill University, Ste. Anne de Bellevue, Quebec, H9X 3V9, Canada.
authors.forename: Luis B
authors.initials: LB
authors.lastname: Agellon
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.|Department of Pediatrics, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: Marek
authors.initials: M
authors.lastname: Michalak
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D005355:Fibrosis; D051379:Mice; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1 / Q000378:metabolism
chemical_list: D037282:Calreticulin; D015815:Cell Adhesion Molecules; C082838:Postn protein, mouse; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D003094:Collagen; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases