Affiliation:
1. Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados-Instituto Politécnico Nacional, Mexico City, Mexico; and
2. Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Mexico City, Mexico
Abstract
Ca+mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca2+ATPase (SERCA2a) has been associated with the development of left ventricular diastolic dysfunction in insulin-resistant cardiomyopathy. However, the molecular causes underlying SERCA2a alterations induced by insulin resistance and related metabolic disorders, such as metabolic syndrome (MetS), are not completely understood. In this study, we used a sucrose-fed rat model of MetS to test the hypothesis that decreased SERCA2a activity is mediated by elevated oxidative stress produced in the MetS heart. Production of ROS and cytosolic Ca2+concentration were recorded in left ventricular myocytes using confocal imaging. The level of SERCA2a oxidation was determined in left ventricular homogenates by biotinylated iodoacetamide labeling. Compared with control rats, sucrose-fed rats exhibited several characteristics of MetS, including central obesity, insulin resistance, hyperinsulinemia, and hypertriglyceridemia. Moreover, relative to myocytes from control rats, myocytes from MetS rats exhibited elevated basal production of ROS accompanied by slowed cytosolic Ca2+removal, reflected by prolonged Ca2+transients. The slowed cytosolic Ca2+removal was associated with a significant decrease in SERCA2a-mediated Ca2+reuptake and increased SERCA2a oxidation. Importantly, myocytes from MetS rats treated with the antioxidant N-acetylcysteine showed normal ROS levels and SERCA2a-mediated Ca2+reuptake as well as accelerated cytosolic Ca2+removal. These data suggest that elevated oxidative stress may induce oxidative modifications on SERCA2a leading to abnormal function of this protein in the MetS heart.
Publisher
American Physiological Society
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology
Cited by
66 articles.
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