title: IL-6/STAT3 signaling in mice with dysfunctional type-2 ryanodine receptor.
abstract: Mice with genetically modified cardiac ryanodine receptor (Ryr2 (ADA/ADA) mice) are impaired in regulation by calmodulin, develop severe cardiac hypertrophy and die about 2 weeks after birth. We hypothesized that the interleukin 6 (IL-6)/signal transducer and activator of transcription-3 (STAT3) signaling pathway has a role in the development of the Ryr2 (ADA/ADA) cardiac hypertrophy phenotype, and determined cardiac function and protein levels of IL-6, phosphorylation levels of STAT3, and downstream targets c-Fos and c-Myc in wild-type and RyR2 (ADA/ADA) mice, mice with a disrupted IL-6 gene, and mice treated with STAT3 inhibitor NSC74859. IL-6 protein levels were increased at postnatal day 1 but not day 10, whereas pSTAT3-Tyr705/STAT3 ratio and c-Fos and c-Myc protein levels increased in hearts of 10-day but not 1-day old Ryr2 (ADA/ADA) mice compared with wild type. Both STAT3 and pSTAT3-Tyr705 accumulated in the nuclear fraction of 10-day old Ryr2 (ADA/ADA) mice compared with wild type. Ryr2 (ADA /ADA) /IL-6(-/-) mice lived 1.5 times longer, had decreased heart to body weight ratio, and reduced c-Fos and c-Myc protein levels. The STAT3 inhibitor NSC74859 prolonged life span by 1.3-fold, decreased heart to body weight ratio, increased cardiac performance, and decreased pSTAT-Tyr705/STAT3 ratio and IL-6, c-Fos and c-Myc protein levels of Ryr2 (ADA /ADA) mice. The results suggest that upregulation of IL-6 and STAT3 signaling contributes to cardiac hypertrophy and early death of mice with a dysfunctional ryanodine receptor. They further suggest that STAT3 inhibitors may be clinically useful agents in patients with altered Ca(2+) handling in the heart.
authors.affiliation: Department of Biochemistry & Biophysics; University of North Carolina ; Chapel Hill, NC USA.
authors.forename: Tai-Qin
authors.initials: TQ
authors.lastname: Huang
authors.affiliation: Department of Pathology and Laboratory Medicine; University of North Carolina ; Chapel Hill, NC USA.
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.affiliation: Department of Biochemistry & Biophysics; University of North Carolina ; Chapel Hill, NC USA.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meissner
keywords: IL-6; NSC74859; S3I-201; STAT3; calmodulin; cardiac hypertrophy; cardiac ryanodine receptor