Effects of JMJD3 on DOX-induced cardiotoxicity through regulating STAT3 / 中国药理学通报

ABSTRACT

Aim To investigate the regulatory relationship and mechanism of JMJD3 and STAT3 in DOX-induced cardiotoxicity. Methods To establish the model of cardiotoxicity in vitro and in vivo, H9C2cells were treated with DOX(1 μmol · L-1) for 12 hours; Sprague-Dawley rats were subcutaneously injected with a cumulative dose of 15 mg · kg-1DOX. The adenovirus encoding JMJD3 (Ad-JMJD3) was transduced into the rat left ventricle via intramyocardial injection. The recombinant adenovirus (Ad-JMJD3 or Ad-STAT3) infection were used to overexpress JMJD3 or STAT3 in cardiomyocytes. Knockdown JMJD3 was achieved by transfecting with siRNA of JMJD3 in H9C2cells. The method of TMRE was used to detect the mitochondrial membrane depolarization. Results The model of cardiotoxicity was successfully built both in vivo and in vitro by DOX. The mRNA and protein level of JMJD3 in DOX-induced cardiotoxicity both in vivo and in vitro were significantly raised compared with those of control or NC group. Ad-JMJD3 significantly aggravated the damage effect of H9C2cells induced by DOX. JMJD3 knockdown could significantly relieve DOX-induced apoptosis. Ad-STAT3 could obviously attenuate DOX-or Ad-JMJD3-induced apoptosis-related protein expression. Both DOX and Ad-JMJD3 could inhibit the protein expression and phosphorylation level of STAT3. Conclusions DOX caused the up-regulation of protein expression of JMJD3, inhibited STAT3 and p-STAT3 protein expression, thus, aggravating cardiotoxicity.