Dysfunction of cardiac ryanodine receptors in the metabolic syndrome

This study examined the hypothesis that the prediabetic metabolic syndrome alters expression, phosphorylation state and binding affinity of cardiac RyR 2. Real-time PCR and Western blot analysis were used to assess mRNA and protein expression in the left ventricle, right ventricle and right atrium from control ( n = 5) and chronically high-fat-fed ( n = 5) dogs with the metabolic syndrome. Functional integrity of RyR 2 was assessed by RyR 2-Ser 2809 phosphorylation and the receptor's ability to bind [ 3H]ryanodine. We found that RyR 2 phosphorylation at Ser 2809 was significantly elevated in right and left ventricle from high-fat-fed dogs compared to normal control dogs. This hyperphosphorylation was associated with a decrease in RyR 2 binding affinity in right and left ventricle (high-fat diet = 80.2 and 90.5 fmol/mg protein vs. control = 243.6 and 200.9 fmol/mg protein, respectively) and a decrease in cardiac index in exercising dogs. RyR 2 phosphorylation at Ser 2809 and RyR 2 binding affinity were not altered in the right atria of high-fat-fed dogs. In addition, no significant differences in cardiac RyR 2 mRNA or protein expression were noted between groups. These data suggest that alterations in RyR 2 could be an important mechanism of early cardiac dysfunction in obesity and insulin resistance.