Ablation of C/EBP Homologous Protein Attenuates Endoplasmic Reticulum–Mediated Apoptosis and Cardiac Dysfunction Induced by Pressure Overload

Abstract

Background-Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified. Methods and Results-In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2␣, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts. Conclusions-We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload. (Circulation. 2010;122:361-369.)

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Of the other markers of endoplasmic reticulum stress, we looked at CHOP because it has been shown to modify protein translation and mediate endoplasmic reticulum–initiated cell death. Its ablation has been shown to be protective against POL‐induced hypertrophy and HF 30. The expression of the mitochondrial death and mitophagy marker, BNIP3, and the Bax/Bcl‐2 ratio, a marker of increased mitochondrial apoptosis, were uniquely increased in the MOD phenotype as compared with sham (and the CR and MILD phenotypes) (Figure 6C).…”

COX-2–Independent Effects of Celecoxib Sensitize Lymphoma B Cells to TRAIL-Mediated Apoptosis

“…5A). The role of Bax in CHOP-induced apoptosis was suggested from studies using macrophages (41,42) where Bax level increased with ER stress in a CHOPdependent manner (43). Prolonged ER stress can hyperoxidize the ER lumen and directly induce cytotoxic ROS in the cytoplasm.…”

A novel endoplasmic reticulum stress-induced apoptosis model using tunicamycin in primary cultured neonatal rat cardiomyocytes

“…Various stimuli, such as ischemia (2), hypoxia (3), heat shock, genetic mutation (4), oxidative stress (5) and elevated protein synthesis could result in ER dysfunction. Stresses that lead to the impairment of ER function are collectively known as ER stress (6,7). ER stress triggers an evolutionarily conserved response termed the unfolded protein response (UPR), an adaptive mechanism that initially promotes organelle recovery (8).…”