Abstract 10935: Cardiac-Specific Deletion of Suppressor of Cytokine Signaling-3 Prevents Doxorubicin-Induced Cardiomyopathy in Mice
Background: JAK-STAT activating cytokines can prevent the development of cardiomyopathy induced by doxorubicin (DOX). We previously showed that the suppressor of cytokine signaling-3 (SOCS3) is an intrinsic negative regulator of JAK-STAT signaling. Here, we created cardiac-specific SOCS3-knockout mice (SOCS3-CKO) to investigate whether myocardial SOCS3 would play a role in the development of DOX-induced cardiomyopathy.
Methods and Results: DOX-induced cardiomyopathy was induced in wild-type mice (WT) after a single intraperitoneal injection of DOX (15 mg/kg). Western blot analysis revealed that transient STAT3 phosphorylation was associated with SOCS3 induction in WT hearts after DOX administration. At 2 days after DOX administration, real-time PCR of mouse hearts revealed increases in JAK-STAT-activating cytokines including granulocyte-colony stimulating factor (8.5 fold), interleukin-11 (3.0 fold), and leukemia inhibitory factor (2.1 fold). The activation of the STAT3-SOCS3 pathway was closely correlated with elevations in plasma levels of creatine kinase MB (CK-MB) after DOX administration in WT. This suggested an important link between the activation of the STAT3-SOCS3 pathway and the development of DOX-induced cardiac injuries. To clarify the role of myocardial SOCS3, we created cardiac-specific SOCS3 knockout mice (SOCS3-CKO). Elevations of CK-MB were abolished in SOCS3-CKO after DOX administration (p<0.01). We found that, at 14 days after DOX administration, SOCS3-CKO mice showed better fractional shortening (FS) and less fibrosis than WT. (FS: 33.9% vs. 29.4%, p<0.01; cardiac fibrosis area: 2.8% vs. 8.6%, p<0.01). Western blot analysis revealed that the duration and intensity of STAT3 phosphorylation was greater in SOCS3-CKO than WT (p<0.01). Moreover, expression of AMP-activated protein kinase, which plays a key role in regulating both cellular energy metabolism and cardioprotection, was markedly up regulated in SOCS3-CKO more than that in WT after DOX administration (p<0.01).
Conclusion: These results suggest that DOX-induced cardiomyopathy may be prevented by manipulation of SOCS3.
- © 2012 by American Heart Association, Inc.