Abstract 18442: Cardiac-specific SOCS3 Deficiency Leads to Left Ventricular Dysfunction With Advanced Age Through Impaired Autophagy
Introduction: Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of JAK-STAT signaling pathway. Cardiac-specific SOCS3 deficient mice (SOCS3-CKO) spontaneously develop cardiac dysfunction with advanced age.
Hypothesis: We thus evaluated the underlying mechanism of age-related cardiac dysfunction in SOCS3-cKO mice.
Methods: To create SOCS3-CKO mice, SOCS3-flox mice were bred with mice harboring a transgene encoding Cre recombinase driven by the α-myosin heavy chain promoter. Cardiac fibrosis was measured by Sirius-red staining. We evaluated autophagy induction by western blot using an antibody raised against microtubule-associated protein light chain 3 (LC3).
Results: SOCS3-CKO mice were born at the expected Mendelian ratio, but developed cardiac dysfunction estimated by echocardiogram from 25 weeks of age. Cardiac fibrosis was greater in SOCS3-CKO mice compared to control mice (p<0.01). Western blot analysis revealed that increased activation of STAT3 from 25 weeks of age in SOCS3-CKO mice (p<0.01). TUNEL-positive cells were not observed in both control and SOCS3-CKO mice at 35 weeks of age. Expressions of Bax and Bad were comparable between control and SOCS3-CKO mice, indicating that apoptosis is not a main mechanism in the cardiac dysfunction with advanced age in SOCS3-CKO mice. In SOCS3-CKO mice hearts from 25 weeks of age, LC3II/LC3I ratio was significantly decreased (p<0.01). Western blot analysis revealed that expression of parkin and PINK1 but not p62 and Bnip3 were decreased in SOCS3-CKO mice compared with control mice from 25 weeks of age (p<0.01). We found that fasting-induced changes of LC3II/LC3I ratio were correlated with activation of STAT3 in WT mice hearts (p<0.01).
Conclusions: These results suggest that age-related cardiac dysfunction in SOCS3-CKO mice may be due to impaired autophagy through sustained STAT3 activation.
Author Disclosures: S. Nohara: None. H. Yasukawa: None. T. Oba: None. T. Nagata: None. J. Takahashi: None. K. Shimozono: None. T. Minami: None. H. Ohshima: None. S. Kyogoku: None. D. Fukui: None. K. Mawatari: None. Y. Sugi: None. Y. Fukumoto: None.
- © 2015 by American Heart Association, Inc.