miR-146a attenuates apoptosis and modulates autophagy by targeting TAF9b/P53 pathway in doxorubicin-induced cardiotoxicity

Abstract

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of apoptosis and dysregulation of autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting apoptosis and improving autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte apoptosis or basal level of autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate apoptosis and adjust autophagy levels.

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

“…Critically, this silencing (hypermethylation) of genes associated with ciliogenesis and its regulation of signalling and differentiation is not a reversion to the naive SF phenotype, underscoring that ES-62 drives rewiring of a unique and “safe/protective” phenotype of SF in mice undergoing CIA. Similarly, whilst induction of CIA is associated with hypermethylation (silencing) of the promoter region of Taf9b (coactivator and stabilizer of p53 and negatively regulated by miR146 87 ), the promoter and TSS sites respectively of Ccnb3 (G2/mitosis cyclin B3) and MAP3K13 (stabilizes c-Myc to promote survival, proliferation and tumorigenesis 88 ) are hypomethylated: ES-62 inverts the methylation status of all 3 of these genes, reverting to the naïve status of Taf9b and Ccnb3 and the ES-62-CIA-specific phenotype for MAP3K13. Moreover, with respect to the aberrant migration of SFs, the promoter region of MAPK10, a signalling element whose downregulation is associated with migration, invasion and angiogenesis in cancer 89 is hypermethylated in CIA- but not naïve or ES-62-CIA, SFs.…”

Polychemotherapy with Curcumin and Doxorubicin via Biological Nanoplatforms: Enhancing Antitumor Activity

“…Stimulation of molecular pathways such as Akt that promote cell proliferation is of importance in reducing DOX side effects [ 93 ]. Non-coding RNAs such as miRNA-146a are able to prevent apoptotic cell death in improving DOX-mediated cardiotoxicity [ 94 ]. Noteworthy, plant derived-natural products have been extensively applied in improving DOX side effects.…”

Circular RNA_101237 mediates anoxia/reoxygenation injury by targeting let‑7a‑5p/IGF2BP3 in cardiomyocytes

“…2c). Autophagic cell death serves important roles in cardiac diseases, including ischemic heart disease and heart failure (21). The autophagy levels in cells were evaluated following A/R treatment and circRNA_101237 siRNA transfection.…”