title: Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol.
abstract: Increasing evidence indicates that endoplasmic reticulum (ER) stress is involved in various diseases. In the human heart, ischemia/reperfusion has been correlated to ER stress, and several markers of the unfolded protein response (UPR) participate during cardiac remodeling and fibrosis. Here, we used isoproterenol (ISO) injection as a model for in vivo cardiac fibrosis. ISO induced significant cardiomyocyte loss and collagen deposition in the damaged areas of the endocardium. These responses were accompanied by an increase in the protein levels of the luminal ER chaperones BIP and PDI, as well as an increase in the UPR effector CHOP. The use of the chemical chaperone 4-phenylbutyric acid (4-PBA) prevented the activation of the UPR, the increase in luminal chaperones and also, leads to decreased collagen deposition, cardiomyocyte loss into the damaged zones. Our results suggest that cardiac damage and fibrosis induced in vivo by the beta-adrenergic agonist ISO are tightly related to ER stress signaling pathways, and that increasing the ER luminal folding capacity with exogenously administrated 4-PBA is a powerful strategy for preventing the development of cardiac fibrosis. Additionally, 4-PBA might prevent the loss of cardiomyocytes. Our data suggests that the attenuation of ER stress pathways with pharmacological compounds such as the chemical chaperone 4-PBA can prevent the development of cardiac fibrosis and adverse remodeling.
authors.affiliation: FONDAP CEMC, Centro de Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
authors.forename: Pedro
authors.initials: P
authors.lastname: Ayala
authors.forename: José
authors.initials: J
authors.lastname: Montenegro
authors.forename: Raúl
authors.initials: R
authors.lastname: Vivar
authors.forename: Alan
authors.initials: A
authors.lastname: Letelier
authors.forename: Pablo Aránguiz
authors.initials: PA
authors.lastname: Urroz
authors.forename: Miguel
authors.initials: M
authors.lastname: Copaja
authors.forename: Deisy
authors.initials: D
authors.lastname: Pivet
authors.forename: Claudio
authors.initials: C
authors.lastname: Humeres
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Vicencio
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
authors.forename: Guillermo
authors.initials: G
authors.lastname: Díaz-Araya
mesh_terms: D000318:Adrenergic beta-Agonists / Q000633:toxicity*; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D018832:Molecular Chaperones / Q000737:chemistry; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D010654:Phenylbutyrates / Q000627:therapeutic use*; D017510:Protein Folding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; C497251:Ddit3 protein, rat; D018832:Molecular Chaperones; D010654:Phenylbutyrates; D051742:Transcription Factor CHOP; C075773:4-phenylbutyric acid; D007545:Isoproterenol