TGFB2-AS1 binding to MED1 promotes doxorubicin-induced cardiomyocyte apoptosis via BMP7 pathway

Doxorubicin-induced cardiotoxicity (DIC) is similar to dilated cardiomyopathy (DCM) in morphological and functional defects, eventually progressing to heart failure. Recently, intensive investigation showed that specific expression profiles of lncRNA have been closely related to cardiovascular disease, but many gaps remain, including the emerging roles of lncRNA in DIC. We identified TGFB2-AS1 as a highly conserved regulator of DCM by reanalyzing publicly available RNA sequencing datasets from GEO and producing conservation scores of lncRNAs using PHAST software. TGFB2-AS1 expression is dramatically increased in murine and cell models, and TGFB2-AS1 has a pro-apoptotic effect in vitro. Moreover, TGFB2-AS1 mediated apoptosis via the BMP7 pathway by activating the Smad1/5/9 phosphorylation to upregulate the target gene expression Id2. Recombinant human bone morphogenetic protein (rhBMP-7) aggravates doxorubicin-induced cardiomyocyte apoptosis, and knockdown of BMP7 significantly reverses the pro-apoptotic effect of TGFB2-AS1 overexpression in vitro. Mechanistically, we found that TGFB2-AS1 combines with transcriptional co-activator MED1, promoting H3K27 acetylation modification level in the promoter of the BMP7 gene and then facilitating BMP7 transcription. Collectively, this study illuminates that TGFB2-AS1 is an evolutionarily conserved long noncoding RNA with a previously unappreciated role in promoting the apoptotic phenotype of DIC and sheds light on the more effective clinical application of doxorubicin.