FTO ameliorates doxorubicin-induced cardiotoxicity by inhibiting ferroptosis via P53-P21/Nrf2 activation in a HuR-dependent m6A manner.

Doxorubicin (DOX)-induced cardiotoxicity seriously limits its clinical applicability, and no therapeutic interventions are available. Ferroptosis, an iron-dependent regulated cell death characterised by lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. N6-methyladenosine (m6A) methylation is the most frequent type of RNA modification and involved in DOX-induced ferroptosis, however, its underlying mechanism remains unclear. P21 was recently found to inhibit ferroptosis by interacting with Nrf2 and is regulated in a P53-dependent or independent manner, such as through m6A modification. In the present study, we investigated the mechanism underlying m6A modification in DOX-induced ferroptosis by focusing on P21. Our results show that fat mass and obesity-associated protein (FTO) down-regulation was associated with DOX-induced cardiotoxicity. FTO over-expression significantly improved cardiac function and cell viability in DOX-treated mouse hearts and H9C2 cells. FTO over-expression significantly inhibited DOX-induced ferroptosis, and the Fer-1 inhibition of ferroptosis significantly reduced DOX-induced cardiotoxicity. P21 was significantly upregulated by FTO and activated Nrf2, playing a crucial role in the anti-ferroptotic effect. FTO upregulated P21/Nrf2 in a P53-dependent manner by mediating the demethylation of P53 or in a P53-independent manner by mediating P21/Nrf2 directly. Human antigen R (HuR) is crucial for FTO-mediated regulation of ferroptosis and P53-P21/Nrf2. Notably, we also found that P21 inhibition in turn inhibited HuR and P53 expression, while HuR inhibition further inhibited FTO expression. RNA immunoprecipitation assay showed that HuR binds to the transcripts of FTO and itself. Collectively, FTO inhibited DOX-induced ferroptosis via P21/Nrf2 activation by mediating the m6A demethylation of P53 or P21/Nrf2 in a HuR-dependent manner and constituted a positive feedback loop with HuR and P53-P21. Our findings provide novel insight into key functional mechanisms associated with DOX-induced cardiotoxicity and elucidate a possible therapeutic approach.

Mechanistic insights into heat shock protein 27, a potential therapeutic target for cardiovascular diseases.

Heat shock protein 27 (HSP27) is a small chaperone protein that is overexpressed in a variety of cellular stress states. It is involved in regulating proteostasis and protecting cells from multiple sources of stress injury by stabilizing protein conformation and promoting the refolding of misfolded proteins. Previous studies have confirmed that HSP27 is involved in the development of cardiovascular diseases and plays an important regulatory role in this process. Herein, we comprehensively and systematically summarize the involvement of HSP27 and its phosphorylated form in pathophysiological processes, including oxidative stress, inflammatory responses, and apoptosis, and further explore the potential mechanisms and possible roles of HSP27 in the diagnosis and treatment of cardiovascular diseases. Targeting HSP27 is a promising future strategy for the treatment of cardiovascular diseases.

Optical coherence tomography-guided drug coated balloon in non-small de novo coronary artery lesions: a prospective clinical research.

PURPOSE: The combined use of drug coated balloon (DCB) and optical coherence tomography (OCT) for the treatment of non-small coronary de novo lesion remains to be evaluated. We investigated the safety and efficacy of OCT-guided DCB in non-small coronary de novo lesion patients with predilation of cutting balloon. METHODS: https://clinicaltrials.gov/, ClinicalTrials.gov Identifier: NCT04795144. This study was a prospective, and open-label study. We enrolled patients with non-small de novo lesions treated with OCT-guided DCB. The non-small de novo lesions indicated vessel lesions with a diameter ≥ 2.5 mm. The primary endpoints were the success rate of the procedure and the occurrence of target lesion revascularization. The secondary endpoints were myocardial infarction, cardiac death, and major adverse cardiac events (MACE) within 3 months after the procedure. RESULTS: At the Second Hospital of Jilin University, we enrolled 54 patients (54 lesions) with non-small de novo lesions who were treated with OCT-guided DCB from October 2018 to June 2019. A total of 52 patients were successfully treated with DCB-only strategy, while 2 patients turned to bailout stenting. A total of 21 patients had undergone angiography 3 months after the procedure with the late lumen loss of 0.24±0.57 mm. There was no statistically significant difference in minimal lumen diameter (MLD) between post-DCB and at 3-month angiographic follow-up (2.25±0.40 mm vs 2.04±0.54 mm; P = 0.110). Only 1 patient developed restenosis with the incidence of MACE rate of only 1.92% (n = 1). There was no significant difference in the stenosis of the lumen diameter of the target lesion vessel between 3 months after operation and immediately after operation. CONCLUSIONS: Our study showed that OCT-guided DCB with cutting balloon under guidance may be a novel approach in non-small de novo coronary artery disease.