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

Abstract

Abstract. Apoptosis plays a critical role in the pathogenesis of chronic myocardial ischemia (cMI) and heart failure (HF). Endoplasmic reticulum stress (ERS) is one of the newly defined signaling pathways which initiate apoptosis. Previous studies have shown that ERS-associated apoptosis is involved in the pathogenesis of HF induced by pressure-overload and acute myocardial infarction. Also, in vitro experiments have proved that ischemia is a strong stimulus of ERS. This study aimed to demonstrate whether ERS-associated apoptosis is involved in the pathogenesis of cMI-induced HF. We established a HF model induced by cMI in mini pigs via placement of an ameroid constrictor around the proximal anterior descending branch of the left coronary artery (LAd). Furthermore, we used myocardial perfusion imaging, echocardiographic and hemodynamic measurements, hematoxylin-eosin staining, and terminal deoxynucleotidyl transferase-mediated dNA nick-end labeling staining to identify the existence of myocardial ischemia and cardiac dysfunction and of enhanced apoptosis in the ischemic heart. We performed immunohistochemistry, Western blot, and real-time PcR to analyze the hallmark of ERS glucose-regulated protein 78 (GRP78). The ERS-associated apoptotic pathways, ccAAT/enhancerbinding protein homologous protein (cHOP), caspase-12, and c-Jun NH 2 -terminal kinase 1 (JNK1) were also examined. We found that all three of these pathways were activated and that GRP78 protein and mRNA levels were significantly enhanced in the myocardium of HF mini pigs induced by cMI. These results suggest that ERS is present in the cMI-induced HF pig model, and that ERS-associated apoptosis is involved in the pathophysiology of HF induced by cMI.

Berberine inhibits cardiac remodeling of heart failure after myocardial infarction by reducing myocardial cell apoptosis in rats

“…Previous findings have confirmed ERS and ERS-induced myocardial cell apoptosis existed in the pathological process of heart failure, which is manifested as the increased GRP78 expression (25,26) of ERS response and the activation of ERS-mediated CHOP and caspase-12 pathways (12,27). The rat model of heart failure after myocardial infarction was established in this experiment.…”

“…ImageJ software (version X; Media Cybernetics, Silver Spring, MD, USA) was employed for determination of bands grey values. Primer sequences used in this study was according to previous reports (11,12). …”

“…Therefore, the inhibition of myocardial cell apoptosis has important clinical significance for the reduction of cardiac remodeling and improvement of cardiac function. Recent studies have shown that endoplasmic reticulum stress (ERS) is associated with heart failure, and ERS-mediated myocardial cell apoptosis is an important aspect of cardiac remodeling (11,12), thus inhibiting the ERS-mediated myocardial cell apoptosis is of great importance for improvement of cardiac function.…”

Endoplasmic Reticulum Stress Induces Different Molecular Structural Alterations in Human Dilated and Ischemic Cardiomyopathy

“…GRP78 is an ER chaperone that is used as a marker for ER stress [25], [26]. Under non-stressed conditions, GRP78 is bound to IRE1, PERK, and ATF6 and maintains them in an inactive state.…”

Extracellular Vesicle Injection Improves Myocardial Function and Increases Angiogenesis in a Swine Model of Chronic Ischemia

“…Chronic myocardial ischemia leads to cardiomyocyte apoptosis and necrosis, left ventricular remodeling, heart failure, and reduced ejection fraction 1. Current treatment modalities to increase blood flow to chronically ischemic myocardial tissue include revascularization procedures such as coronary bypass grafting, percutaneous coronary intervention, and transmyocardial revascularization.…”