Background: Suppressor of cytokine signaling-3 (SOCS3) is an intrinsic negative-feedback regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that myocardial SOCS3 plays an important role in cardiac hypertrophy and survival; however, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology.

Methods and results: To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 52 weeks of age (p<0.05). Echocardiographic analyses of sm-SOCS3-KOmice showed significantly decreased cardiac function compared with wild-typefrom 52 weeks of age (p<0.05). Interestingly, Sirius-red staining revealed that thickness of pericardium in sm-SOCS3-KOmice was markedly greater compared with wild-typemice at 52 weeks of age (p<0.05). Cardiac interstitial fibrosis in sm-SOCS3-KOmice was also greater compared with wild-typemice (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KOhearts compared with wild-typemice at 52 weeks of age (p<0.05), whereas no significant differences were observed at 7 weeks of age. Immunostaining revealed that phosphorylated STAT3 positive cells were in thickened pericardial area in sm-SOCS3-KOhearts. Some infiltrated inflammatory cells were also found in thickened pericardial area in sm-SOCS3-KOmice hearts.

Conclusion: These results suggest that STAT3 and its negative-feedback regulator SOCS3 in smooth muscle cells play an important role in the pathogenesis of pericardial fibrosis and cardiac dysfunction.