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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.
Highlights
Chronic myocardial ischemia has become the leading cause of heart failure
The Sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) gene, transferred to ischemic myocardium, attenuates the apoptosis of ischemic myocardium compared with the ischemic heart disease (IHD)+enhanced green fluorescent protein (EGFP) group, the number of apoptotic myocardial cells is still greater in the IHD+SERCA2a group than in the control group
IHD model induced by chronic occlusion of left anterior descending (LAD) coronary artery, we found that the protein level and activity of SERCA2a in the ischemic myocardium was decreased
Summary
Chronic myocardial ischemia has become the leading cause of heart failure. In China, more than half of the patients with heart failure have coronary artery heart disease [1]. These patients suffer from ischemic heart disease (IHD), which leads to the further deterioration of cardiac function. The pathogenesis of IHD is a chronic and complex process, which may involve abnormalities in energy metabolism, altered expression or function of contractile proteins, ventricular remodeling and myocardial apoptosis [2]. Sarco/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), which is primarily responsible for sarcoplasmic reticulum Ca2+ uptake, was reported to be decreased in protein level or activity in the ischemic myocardium in various animals and humans [4,5,6,7]. Vectormediated gene transfer to increase SERCA2a expression or the use of transgenic animals with SERCA2a overexpres-
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