Endoplasmic Reticulum Stress as a Novel Therapeutic Target in Heart Diseases

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.

mTORC1 serves ER stress-triggered apoptosis via selective activation of the IRE1–JNK pathway

“…7 Interestingly, these diseases are also considered as ER stress-related disorders. [8][9][10][11] Rapamycin could exert therapeutic effects via modulating ER stress and/or subsequent UPR. However, currently, relationship between ER stress and mTORC1 remains elusive.…”

Involvement of endoplasmic reticulum stress-associated apoptosis in a heart failure model induced by chronic myocardial ischemia

“…It has been demonstrated that the ERS pathways are activated during the pathogenesis of pressure-overload or AMI-induced HF, although this conclusion has been based on observations in in vitro or in small animal in vivo models (20)(21)(22)(23). In the current study, we established a large animal model of cMI-induced HF by ameroid constrictor placement in mini pig, and we performed echocardiographic and hemodynamic measurements to confirm the existence of cardiac dysfunction and myocardial hematoxylin-eosin staining to identify the histological changes of cMI and HF.…”

“…Ischemia induces myocardial apoptosis, which results in loss of cardiomyocytes, leading to the impairment of cardiac systolic and diastolic functions. A few studies have also demonstrated that ischemia, along with the deprivation of oxygen, nutrition and energy supply, lead to the activation of the ERS pathways in cultured cardiomyocytes or hearts in vitro (17,18,(20)(21)(22)(23). These results and the increasing incidence of cMI-related HF prompted us to examine whether ERS-specific apoptotic signaling is involved in the heart of cMI-induced HF.…”

Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells

“…CHOP represses the expression of anti-apoptotic proteins Bcl-2 and Bnip3, as well as direct transcriptional induction and translocation to the ER membrane of Bim, a proapoptotic BH3-only protein of the Bcl-2 family (25). It has been reported that overexpression of CHOP is sufficient to induce cell death in response to ER stress (25). Therefore, CHOP is the key molecule for inducing apoptosis during ER stress (26).…”

“…PERK, IRE1 and ATF6); however, upon accumulation of unfolded proteins, GRP78 dissociates from these molecules, leading to their activation. As a chaperon, GRP78, which has a conserved ATPase domain and a peptide-binding domain, recognizes and binds to proteins with hydrophobic residues in the unfolded regions (25,26). Regarding GRP78 transcription, the GRP promoters contain multiple copies of the ER stress response element (ERSE) (27).…”