Endoplasmic reticulum stress as a novel therapeutic target in heart diseases

A. Tóth, Philip Nickson, Adel Mandl, Mark L. Bannister, K. Tóth, Peter Erhardt

Research output: Contribution to journalArticle

97 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)205-218
Number of pages14
JournalCardiovascular and Hematological Disorders - Drug Targets
Volume7
Issue number3
DOIs
Publication statusPublished - Sep 2007

Fingerprint

Endoplasmic Reticulum Stress
Unfolded Protein Response
Heart Diseases
Puma
Endoplasmic Reticulum
Apoptosis
Reperfusion
Cardiac Myocytes
Proteins
Therapeutics
Ischemia
Heart Failure
Protein Refolding
Calcium Signaling
Protein Folding
Cardiomegaly
Reperfusion Injury
Brain Ischemia
Organelles
Homeostasis

Keywords

  • Apoptosis
  • Bc1-2
  • ER stress
  • Heart disease
  • Puma
  • UPR

ASJC Scopus subject areas

  • Molecular Medicine
  • Cardiology and Cardiovascular Medicine
  • Hematology
  • Pharmacology

Cite this

Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. / Tóth, A.; Nickson, Philip; Mandl, Adel; Bannister, Mark L.; Tóth, K.; Erhardt, Peter.

In: Cardiovascular and Hematological Disorders - Drug Targets, Vol. 7, No. 3, 09.2007, p. 205-218.

Research output: Contribution to journalArticle

Tóth, A. ; Nickson, Philip ; Mandl, Adel ; Bannister, Mark L. ; Tóth, K. ; Erhardt, Peter. / Endoplasmic reticulum stress as a novel therapeutic target in heart diseases. In: Cardiovascular and Hematological Disorders - Drug Targets. 2007 ; Vol. 7, No. 3. pp. 205-218.
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