Attenuation of Endoplasmic Reticulum Stress-Related Myocardial Apoptosis by SERCA2a Gene Delivery in Ischemic Heart Disease

Abstract

Previous studies suggested that endoplasmic reticulum (ER) stress-associated apoptosis plays an important role in the pathogenesis of ischemic heart disease. Gene transfer of sarco/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a) attenuates myocardial apoptosis in a variety of heart failure models. This study is to investigate the effects of SERCA2a gene delivery on the myocardial apoptosis and ER stress pathway in a porcine ischemic heart disease model. Eighteen pigs were either subjected to ameroid implantation in the coronary artery or sham operation. Eight wks after gene delivery, the protein level and activity of SERCA2a were measured. Myocardial apoptosis was determined using terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling assay. Regional myocardial perfusion and function were evaluated by 99m Tc-sestamibi ( 99m Tc-MIBI) single photon emission computed tomography and echocardiography. The ER stress signaling was assessed by Western blot. SERCA2a protein level and activity were significantly decreased in the ischemic myocardium and restored to normal after SERCA2a gene transfer. Restoration of SERCA2a expression significantly improved the cardiac function, although no improvement of regional myocardial perfusion was detected. Restoration of SERCA2a significantly attenuated myocardial apoptosis and reversed the activation of unfolded protein response (UPR) pathway and the ER stress-associated apoptosis pathways. These findings demonstrate a robust role of SERCA2a in attenuation of ischemic myocardial apoptosis, correlating with reverse activation of the ER stress-associated apoptosis pathways, suggesting that the beneficial effects of SERCA2a gene transfer may involve the attenuation of ER stress-associated myocardial apoptosis.

Endoplasmic Reticulum Stress Sensor Protein Kinase R–Like Endoplasmic Reticulum Kinase (PERK) Protects Against Pressure Overload–Induced Heart Failure and Lung Remodeling

“…Thapsigargin, an inhibitor of Serca2a activity 23 , is commonly used to induce ER stress. In the heart, exogenous expression of Serca2a has been shown to attenuate ER stress and CHF in mouse myocardial infarction or pressure overload models 24 , while selective Serca2a gene deletion in cardiomyocytes causes ER stress in cardiomyocytes and promotes CHF 10 . On the other hand, attenuation of ER stress was found to preserve Serca2a expression and cardiomyocyte function in an obesity model 25 suggesting ER stress and impaired ER calcium handling aggravate one another.…”

An Involvement of Oxidative Stress in Endoplasmic Reticulum Stress and Its Associated Diseases

“…Reperfusion of the affected tissues triggers oxidative stress, with production of NO and other reactive oxygen species that result in protein misfolding [100]. NO and other reactive molecules may also modify oxidizable residues such as cysteine in ER-associated Ca 2+ channels including ryanodine receptors and SERCAs, causing ER Ca 2+ depletion, yet another cause of protein misfolding [101]. Edaravone, a potent free-radical scavenger, is well-known for its protective action against lipid peroxidation.…”

Protein Quality Control and Metabolism: Bidirectional Control in the Heart

“…Likewise, we and others have found that Xbp1s is up-regulated in human heart failure of ischemic etiology, suggesting that the UPR is an intrinsic component of the cardiac stress response (Sawada et al, 2010; Wang et al, 2014). Coronary occlusion in pigs induces all three branches of the UPR (Xin et al, 2011). Consistently, activation of ER stress has been observed in rodent models of myocardial infarction.…”