Abstract
Mammalian cardiomyocytes substantially lose proliferative capacity immediately after birth, limiting adult heart regeneration after injury. However, clinical myocarditis appears to be self-limiting with tissue-reparative properties. Here, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model. Three weeks after EAM induction (EAM3w), cardiac tissue displayed infiltration of inflammatory cells with cardiomyocyte apoptosis. However, by EAM5w, the myocardial damage was remarkably attenuated, associated with an increase in cardiomyocytes that were positively stained with cell cycle markers at EAM3w. Cardiomyocyte fate mapping study revealed that the proliferating cardiomyocytes primarily derived from pre-existing cardiomyocytes. Signal transducer and activator of transcription 3 (STAT3) was robustly activated in cardiomyocytes during inflammation, accompanied by induction of interleukin-6 family cytokines. Cardiomyocyte-specific ablation of STAT3 gene suppressed the frequency of cycling cardiomyocytes in the recovery period without influencing inflammatory status, resulting in impaired tissue repair and cardiac dysfunction. Finally, microarray analysis revealed that the expression of regeneration-related genes, metallothioneins and clusterin, in cardiomyocytes was decreased by STAT3 gene deletion. These data show that adult mammalian cardiomyocytes restore regenerative capacity with cell cycle reentry through STAT3 as the heart recovers from myocarditis-induced cardiac damage.
Highlights
Mammalian cardiomyocytes exit from the cell cycle immediately after birth[1, 2]
signal transducer and activator of transcription 3 (STAT3) is phosphorylated at Y705 by Janus kinase (JAK) upon interleukin-6 (IL-6) family cytokine stimulation[6], and phosphorylated STAT3 is translocated to the nucleus to activate transcription of anti-oxidant and anti-apoptotic molecules, such as metallothioneins[7,8,9] and bcl-xL10; no evidence that STAT3 functions as a proliferative factor in adult mammalian cardiomyocytes has been proposed due to their low proliferative/regenerative capacity
We examined whether myocardial recovery was associated with the replenishment of cardiomyocyte density by counting the number of cardiomyocytes in intact regions before experimental autoimmune myocarditis (EAM) induction (EAM0w), in inflamed regions at EAM3w and in post-inflamed regions at EAM5w
Summary
Mammalian cardiomyocytes exit from the cell cycle immediately after birth[1, 2]. the proliferative capacity of cardiomyocytes is limited in adult mammals, explaining the etiology of heart failure. Cardiac homeostasis in adult mammals has been believed to be maintained mainly by protection of cardiomyocytes rather than by their proliferation. In this context, a number of efforts have been made to identify cardioprotective factors to develop novel therapeutic strategies. The involvement of STAT3 in cardiomyocyte proliferation has been addressed exclusively in zebrafish and neonatal mouse hearts[11, 12], because zebrafish and neonatal mouse cardiomyocytes, unlike adult mammals, possess the proliferative capacity and respond to trauma by reentering the cell cycle[13,14,15,16,17]. It is conceivable that adult mammalian hearts show healing capability from injury in myocarditis, the cellular and molecular mechanisms underlying the recovery process are poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
