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

• Published in: Experimental and molecular pathology Vol. 92; no. 1; pp. 97 - 104
• Main Authors: Ayala, Pedro, Montenegro, José, Vivar, Raúl, Letelier, Alan, Urroz, Pablo Aránguiz, Copaja, Miguel, Pivet, Deisy, Humeres, Claudio, Troncoso, Rodrigo, Vicencio, José Miguel, Lavandero, Sergio, Díaz-Araya, Guillermo
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.02.2012; Elsevier
• Subjects: 4-Phenylbutyric acid; Adrenergic beta-Agonists - toxicity; Animals; Biological and medical sciences; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - drug effects; Fibrosis; Fibrosis - chemically induced; Fibrosis - pathology; Fibrosis - prevention & control; Heart; Humans; Investigative techniques, diagnostic techniques (general aspects); Isoproterenol; Isoproterenol - toxicity; Male; Medical sciences; Molecular Chaperones - chemistry; Myocardium - pathology; Myocytes, Cardiac - drug effects; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenylbutyrates - therapeutic use; Protein Folding; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Transcription Factor CHOP - metabolism; 4-Phenylbutyric acid; Heart; ISO; 4-PBA; UPR; Fibrosis; Isoproterenol; ER; ECM; Endoplasmic reticulum stress; Prevention; Anatomic pathology; Isoprenaline; Chaperone; Circulatory system; Endoplasmic reticulum; Stress
• ISSN: 0014-4800; 1096-0945
• DOI: 10.1016/j.yexmp.2011.10.012

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. ► Endoplasmic reticulum stress is involved in cardiac fibrosis induced by isoproterenol. ► 4-Phenylbutyric acid prevents endoplasmic reticulum stress induced by isoproterenol. ► 4-Phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol.