Cardiomyocyte-derived HMGB1 takes a protective role in CVB3-induced viral myocarditis via inhibiting cardiac apoptosis.

Coxsackievirus B3 (CVB3)-induced viral myocarditis (VMC) is characterized by immune cell infiltration and myocardial damage. High mobility group box 1 (HMGB1) is a highly conserved nuclear DNA-binding protein that participates in DNA replication, transcriptional regulation, repair response and inflammatory response in different disease models. To investigate the exact function of HMGB1 in CVB3-induced VMC, we crossed Hmgb1-floxed (Hmgb1f/f ) mice with mice carrying a suitable Cre recombinase transgenic strain to achieve conditional inactivation of the Hmgb1 gene in a cardiomyocyte-specific manner and to establish myocarditis. In this study, we found that cardiomyocyte-specific Hmgb1-deficient (Hmgb1f/f TgCre/+ ) mice exhibited exacerbated myocardial injury. Hmgb1-deficient cardiomyocytes may promote early apoptosis via the p53-mediated Bax mitochondrial pathway, as evidenced by the higher localization of p53 protein in the cytosol of Hmgb1-deficient cardiomyocytes upon CVB3 infection. Moreover, cardiomyocyte Hmgb1-deficient mice are more susceptible to cardiac dysfunction after infection. This study provides new insights into HMGB1 in VMC pathogenesis and a strategy for appropriate blocking of HMGB1 in the clinical treatment of VMC.