Oxidative stress in cardiomyocytes contributes to decreased SERCA2a activity in rats with metabolic syndrome

Ca(+) mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca(2+) 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 i...

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Published in:American journal of physiology. Heart and circulatory physiology 2013-11, Vol.305 (9), p.H1344-H1353
Main Authors: Balderas-Villalobos, Jaime, Molina-Muñoz, Tzindilu, Mailloux-Salinas, Patrick, Bravo, Guadalupe, Carvajal, Karla, Gómez-Viquez, Norma L
Format: Article
Language:English
Subjects:
Animals
Antioxidants - pharmacology
Calcium - metabolism
Calcium Signaling
Calcium-Binding Proteins - metabolism
Cardiovascular disease
Dietary Sucrose
Disease Models, Animal
Down-Regulation
Hyperinsulinism - blood
Hyperinsulinism - enzymology
Hypertriglyceridemia - blood
Hypertriglyceridemia - enzymology
Insulin
Insulin Resistance
Male
Metabolic syndrome
Metabolic Syndrome - blood
Metabolic Syndrome - chemically induced
Metabolic Syndrome - enzymology
Myocytes, Cardiac - drug effects
Myocytes, Cardiac - enzymology
Obesity, Abdominal - blood
Obesity, Abdominal - enzymology
Oxidation-Reduction
Oxidative stress
Oxidative Stress - drug effects
Pathology
Phosphorylation
Rats
Rats, Wistar
Reactive Oxygen Species - metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
Ventricular Dysfunction, Left - enzymology
Ventricular Dysfunction, Left - etiology
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Summary:Ca(+) mishandling due to impaired activity of cardiac sarco(endo)plasmic reticulum Ca(2+) 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 Ca(2+) 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 Ca(2+) removal, reflected by prolonged Ca(2+) transients. The slowed cytosolic Ca(2+) removal was associated with a significant decrease in SERCA2a-mediated Ca(2+) reuptake and increased SERCA2a oxidation. Importantly, myocytes from MetS rats treated with the antioxidant N-acetylcysteine showed normal ROS levels and SERCA2a-mediated Ca(2+) reuptake as well as accelerated cytosolic Ca(2+) 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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00211.2013