【Background and Objective】
Though adult mammalian hearts have the limited regenerative capacity, most patients with myocarditis recover from cardiac dysfunction. In this study, using murine experimental autoimmune myocarditis (EAM) model, we addressed the molecular mechanism of myocardial recovery from myocarditis by focusing on YAP, because YAP plays important roles in cardiomyocyte (CM) proliferation and in cardiac regeneration in neonatal hearts.
【Method＆Results】
To generate EAM model, Balb/c mice were immunized with myosin heavy chain peptides twice. At 3 weeks after the first immunization (EAM3w), inflammatory reaction and myocardial damage peaked. The percentage of YAP positive CMs was increased, while the expression of α-catenin, a negative regulator of YAP, was decreased. We generated tamoxifen-inducible cardiomyocyte-specific YAP conditional knockout mice (YAP CKO mice). Echocardiographic analyses revealed that ejection fraction (EF) was reduced both in wild-type and YAP CKO mice at EAM3w and that wild-type mice, but not YAP CKO mice, showed the recovery of EF at EAM5w. Immunofluorescent microscopic analyses using anti-Ki-67 antibody revealed that the frequency of Ki-67 positive CM decreased in YAP CKO mice, compared with wild-type mice.
【Conclusions】
Myocardial activation of YAP is essential for the recovery from myocarditis.