Interplay between Cardiac Proteostasis and ER Stress Coping Responses

Molecular chaperones are specialized proteins essential for facilitating the correct folding, assembly and disassembly of many cellular proteins and for assuring proteostasis. Genetic mutations or metabolic extremes that cause long term alteration of cellular homeostasis compromise protein folding efficiency. To maintain proteostasis, cells mobilized stress coping responses that includes the unfolded protein response (UPR) in order to prevent accumulation of improperly folded proteins that forms the basis of many diseases. Fibrosis of cardiac tissues 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. We discovered that the mechanism leading to development of fibrosis in a mouse model of heart failure stems from impairment of endoplasmic reticulum (ER) homeostasis, transient activation of the 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 improve prognosis. These findings offer a window for additional interventions that can preserve heart function and extend life span.

Supported by Canadian Institute of Health Research.