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 RyR₂. 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 RyR₂ was assessed by RyR₂-Ser²⁸⁰⁹ phosphorylation and the receptor's ability to bind [³H]ryanodine. We found that RyR₂ phosphorylation at Ser²⁸⁰⁹ 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 RyR₂ 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. RyR₂ phosphorylation at Ser²⁸⁰⁹ and RyR₂ binding affinity were not altered in the right atria of high-fat-fed dogs. In addition, no significant differences in cardiac RyR₂ mRNA or protein expression were noted between groups. These data suggest that alterations in RyR₂ could be an important mechanism of early cardiac dysfunction in obesity and insulin resistance.