Impaired Function of Cardiac Ryanodine Receptors in An Experimental Model of Metabolic Syndrome

Abstract

Metabolic syndrome (MS) has become a global epidemic. In Mexico, the prevalence of MS has increased in the last 10 years together with obesity and type-2 diabetes. MS is a serious health problem due to its related cardiovascular disorders: hypertension and heart failure. The latter is among the major causes of death in Mexico. The molecular mechanisms responsible for MS are unclear but could be related to anomalies in cardiac excitation-contraction coupling (E-C coupling). The cardiac Ca2+ channel, the Ryanodine Receptor (RyR2), is a key macromolecular complex that participates in releasing Ca2+from internal stores and is centrally involved in the modulation of cardiac E-C coupling. Our aim was to examine alterations in the expression level, phosphorylation status, Ca2+ sensitivity and in situ function (Ca2+ sparks and Ca2+ transients) of RyR2 that could explain the cardiac dysfunction associated with MS.MS was induced in our rat model by adding commercially refined sugar (30% sucrose) to their drinking water. The sucrose-fed rats became overweight with an increased accumulation of waist fat and also developed hypertension. Our [3H]ryanodine binding data show that functional RyR2 are decreased in MS rat hearts with slight but insignificant changes in Ca2+ sensitivity. Western Blot analysis confirmed that MS did not alter the phosphorylation status of RyR2 at Serine-2809 normalized with respect to total RyR2. A significant decrease in Ca2+ spark frequency was found in isolated Fluo-3 loaded cardiomyocytes of MS rats. In addition Ca2+ transients elicited at frequencies of 0.5, 1, and 2 Hz were also impaired, suggesting a diminished Ca2+ cycling condition in MS cardiomyocytes.Overall, the decreased RyR2 expression together with the impaired RyR2 function could account for the reported poor overall cardiac outcome found in this animal model of MS.