STAT3 activation in cardiac hypertrophy induced by ryanodine receptor 2 mutation

Abstract

Ryanodine receptor 2 (RyR2) is a 2,200 kDa ion channel that is activated during an action potential to release Ca2+ required for cardiac muscle to contract. RyR2 mutant mice (RyR2‐ W3587A/L3591D/F3603A or Ryr2ADA) impaired in regulation by calmodulin show cardiac hypertrophy and survive about two weeks. We hypothesized that signal transducer and activator of transcription‐3 (STAT3) may play a role in cardiac hypertrophy of Ryr2ADA/ADA mice. We found that the protein expression levels of pSTAT3 and IL‐6, an upstream effector of STAT3, were increased in 10 day old Ryr2ADA/ADA mouse hearts but STAT3 expression was maintained. Corresponding with an increased nuclear translocation of pSTAT3 in Ryr2ADA/ADA mice, mRNA expression levels of ANP and c‐fos in left ventricular hearts were greatly increased in Ryr2ADA/ADA mice. The mutant mice also showed higher protein expression level of c‐fos and Chip assay indicated enrichment of STAT3 target genes ANP and c‐fos in the nuclei. The results suggest that activated STAT3 signaling pathway may play an important role in the development of cardiac hypertrophy in mice with dysfunctional ryanodine receptor. Supported by NIH.