Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol

Pedro Ayala, José Montenegro, Raúl Vivar, Alan Letelier, Pablo Aránguiz Urroz, Miguel Copaja, Deisy Pivet, Claudio Humeres, Rodrigo Troncoso, José Miguel Vicencio, Sergio Lavandero, Guillermo Díaz-Araya

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)97-104
Number of pages8
JournalExperimental and Molecular Pathology
Volume92
Issue number1
DOIs
StatePublished - Feb 2012
Externally publishedYes

Keywords

  • 4-Phenylbutyric acid
  • Endoplasmic reticulum stress
  • Fibrosis
  • Heart
  • Isoproterenol

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Clinical Biochemistry

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