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PLoS One. 2016 Jul 21;11(7):e0159682. doi: 10.1371/journal.pone.0159682. eCollection 2016.

Inhibition of the Unfolded Protein Response Mechanism Prevents Cardiac Fibrosis.

Author information

1
Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
2
School of Dietetics and Human Nutrition, McGill University, Ste. Anne de Bellevue, Quebec, H9X 3V9, Canada.
3
Department of Pediatrics, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
4
Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.

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.

METHODOLOGY/PRINCIPAL FINDINGS:

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.

PMID:
27441395
PMCID:
PMC4956237
DOI:
10.1371/journal.pone.0159682
[Indexed for MEDLINE]
Free PMC Article

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