Abstract 13219: Adult Mammalian Hearts Restore Intrinsic Regenerative Capacity Through Signal Transducer and Activation of Transcription 3 in the Resolution Phase of Myocarditis
Background and Aims: It is widely accepted that mammalian cardiomyocytes can hardly proliferate in response to injury, which limits regeneration of the heart. On the contrary, spontaneous recovery in cardiac function is frequently observed in clinical settings of myocarditis. Therefore, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model.
Methods and Results: EAM was induced by immunizing 8 week old male BALB/c mice with α-myosin heavy chain twice. Three weeks after the first immunization (EAM3w), cardiac tissue was severely disrupted by infiltration of inflammatory cells, and substantial loss of cardiomyocytes was observed. However, cardiomyocytes displayed proliferative signature as demonstrated by increased expression of proliferative markers, i.e., Ki-67 and Aurora B, and BrdU incorporation at EAM3w, leading to dramatic tissue restoration at EAM5w. Consistently, the number of cardiomyocytes in the inflamed area was significantly increased at EAM5w compared to EAM3w. Additionally, we employed genetic cell fate mapping methods to trace pre-existing cardiomyocytes with YFP expression and found that pre-existing cardiomyocytes, rather than precursors/stem cells, were the source of proliferating cardiomyocytes at EAM3w. Immunoblot analyses for isolated cardiomyocytes demonstrated that signal transducer and activation of transcription 3 (STAT3), but not Akt or ERK, signaling was robustly activated in the inflamed heart, in consistence with upregulation of various IL-6 family cytokines. Conditional ablation of STAT3 in cardiomyocytes significantly suppressed cardiomyocyte proliferation at EAM3w without preventing the resolution of inflammation, resulting in impaired tissue restoration and cardiac dysfunction at EAM5w.
Conclusions: Adult mammalian hearts restored intrinsic regenerative capacity in response to myocardial inflammation. STAT3 plays a critical role in cardiomyocyte proliferation in the recovery process from inflammation-induced cardiac damage.
Author Disclosures: A. Miyawaki: None. M. Obana: None. Y. Mitsuhara: None. A. Orimoto: None. Y. Nakayasu: None. T. Yamashita: None. S. Fukada: None. M. Maeda: None. Y. Sakata: None. H. Nakayama: None. Y. Fujio: None.
- © 2016 by American Heart Association, Inc.