Abstract

Doxorubicin-induced cardiotoxicity (DIC) features cardiomyocyte loss and maladaptive remodeling. Mitochondrial damage, oxidative stress, autophagy, and different types of cell death, including ferroptosis, pyroptosis, and apoptosis, are recognized as the principal biological mechanisms contributing to DIC, in which disrupted mitochondrial dynamics play a pivotal role. The role of long noncoding RNAs (lncRNAs) in DIC is becoming more well understood; however, the function of TGFB2-AS1 remains unclear. Here, DIC was established in doxorubicin-treated male C57BL/6 mice and in doxorubicin-treated AC16/HL-1 cardiomyocytes. TGFB2-AS1 expression and subcellular localization were determined, and gain- and loss-of-function analyses were performed. Flow cytometry was used to quantify apoptosis and intracellular reactive oxygen species (ROS), and apoptosis-associated proteins and mitochondrial dynamics regulators were assessed by immunoblotting. Mitochondrial morphology was visualized using MitoTracker staining. Bone morphogenic protein 7 (BMP7) signaling was evaluated via recombinant BMP7 supplementation and BMP7 knockdown. Cardiac structure and injury were evaluated by echocardiography and histology. TGFB2-AS1 expression was markedly upregulated in DIC models, and TGFB2-AS1 overexpression exacerbated doxorubicin-induced hypertrophy, apoptosis, ROS accumulation, and mitochondrial fragmentation, whereas TGFB2-AS1 silencing partially reversed these effects. Mechanistically, TGFB2-AS1 knockdown restored BMP7/Smad1/5/9– inhibitor of DNA binding protein 2 (Id2) signaling, and BMP7 depletion attenuated the cardioprotective effects of TGFB2-AS1 silencing. Consistently, BMP7 supplementation mitigated cardiomyocyte apoptosis and Drp1-associated mitochondrial fission in vitro and improved doxorubicin-induced remodeling in vivo through the activation of BMP7/Smad signaling. Collectively, TGFB2-AS1 promotes DIC by suppressing BMP7/Smad/Id2 signaling and enhancing mitochondrial fission,