Abstract 12354: Cardiac STAT3 Activation in Subacute Phase of Myocardial Infarction was Required for the Suppression of Adverse Cardiac Remodeling
Backgroud: Cardiac STAT3 plays crucial roles in cardioprotection against acute injury after MI. However, mutated gp130-induced continuous STAT3 activation resulted in serious cardiac damage in the subacute phase of MI. Here, we examined the biological significance of intrinsic cardiac STAT3 during subacute/chronic phase of MI in a time specific manner using tamoxifen inducible cardiac specific STAT3 knockout mice (iCKO).
Methods and Results: MI was generated by ligating the left coronary artery in mice. Immunoblotting revealed that STAT3 was rapidly activated in the myocardium, and that its activation was sustained to subacute phase after MI. To clarify the impact of cardiac STAT3 in subacute phase of MI, STAT3 gene was ablated by administering tamoxifen to α-MHC-MerCreMer/STAT3flox/flox for 14 consecutive days from post-infarct day 11. As control mice, α-MHC-MerCreMer/STAT3wild/wild mice were used. Importantly, MI-induced cardiac STAT3 activation was significantly decreased in iCKO mice at day 24. Intriguingly, the mortality was accelerated in iCKO mice compared with control mice, coincident with increased heart weight/body weight. Masson’s trichrome staining demonstrated that cardiac STAT3 ablation resulted in severe fibrosis (iCKO; 58.3±6.7%, control; 40.8±9.3%, p<0.01, n=7 for control, n=8 for iCKO). Moreover, Echocardiography clarified that cardiac function was deteriorated in iCKO mice (FS: iCKO; 20.6±4.1%, control; 29.1±6.0%, p<0.05, n=10 for control, n=11 for iCKO). In border area, marked myocardial injuries, including ROS production and hypertrophy, were observed in iCKO mice. Finally, immunohistochemistry revealed that capillary density was decreased in iCKO mice (iCKO; 1724.2±119.4 capillaries/mm2, control; 2110.5±77.7 capillaries/mm2, p<0.01, n=30 fields from 5 mice for each).
Conclusions: Cardiac STAT3 ablation in subacute phase of MI aggravated cardiac remodeling. The augmentation of STAT3 activity could be a therapeutic strategy for the prevention from the onset of chronic heart failure.
Author Disclosures: D. Enomoto: None. M. Obana: None. A. Miyawaki: None. T. Mohri: None. M. Maeda: None. Y. Sakata: None. H. Nakayama: None. Y. Fujio: Research Grant; Modest; DAIICHI SANKYO COMPANY, LIMITED, Takeda Pharmaceutical Company Limited, Pfizer Inc. Research Grant; Significant; Bristol-Myers Squibb Company.
- © 2015 by American Heart Association, Inc.