Cardiovascular & Hematological Disorders-Drug Targets

(Formerly Current Drug Targets - Cardiovascular & Hematological Disorders)

Garry X. Shen  
University of Manitoba
Winnipeg, MB
Canada

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Endoplasmic Reticulum Stress as a Novel Therapeutic Target in Heart Diseases

Author(s): Ambrus Toth, Philip Nickson, Adel Mandl, Mark L. Bannister, Kalman Toth, Peter Erhardt.

Abstract:

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for the synthesis and folding of proteins as well as calcium storage and signaling. Perturbations of ER function cause ER stress leading to the unfolded protein response (UPR), which includes inhibition of protein synthesis, protein refolding and clearance of misfolded proteins. The UPR aims at restoring cellular homeostasis, however, prolonged ER stress can trigger apoptosis. ER stress-induced apoptosis has been implicated in the pathogenesis of various diseases such as brain ischemia/reperfusion, neurodegeneration, diabetes and, most recently, myocardial infarction and heart failure. Initial events leading to UPR and apoptosis in the heart include protein oxidation and disturbed calcium handling upon ischemia/reperfusion, and forced protein synthesis during cardiac hypertrophy. While XBP-1 and ATF6-mediated induction of ER chaperones seems to protect the heart from ischemia/reperfusion injury, the PERK/ATF4/CHOP branch of the UPR might transmit proapoptotic signals. The precise mechanism of ER stress-induced cardiomyocyte apoptosis remains elusive, however, recent data suggest that the mitochondrial apoptotic machinery is recruited through the upregulation of Puma, a proapoptotic member of the Bcl-2 family. Importantly, suppression of Puma activity prevented both ER stress and ischemia/reperfusion-induced cardiomyocyte loss, highlighting the ER stress pathways as potential therapeutic targets in cardiovascular diseases.

Keywords: Heart disease, ER stress, UPR, apoptosis, Bcl-2, Puma

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Article Details

VOLUME: 7
ISSUE: 3
Year: 2007
Page: [205 - 218]
Pages: 14
DOI: 10.2174/187152907781745260
Price: $58