Cardiomyocyte death is a fundamental progress in cardiomyopathy. However, the mechanism of triggering the death of myocardial cells remains unclear. Ferroptosis, which is the nonapoptotic, iron-dependent, and peroxidation-driven programmed cell death pathway, that is abundant and readily accessible, was not discovered until recently with a pharmacological approach. New researches have demonstrated the close relationship between ferroptosis and the development of many cardiovascular diseases, and several ferroptosis inhibitors, iron chelators, and small antioxidant molecules can relieve myocardial injury by blocking the ferroptosis pathways. Notably, ferroptosis is gradually being considered as an important cell death mechanism in the animal models with multiple cardiomyopathies. In this review, we will discuss the mechanism of ferroptosis and the important role of ferroptosis in cardiomyopathy with a special emphasis on the value of ferroptosis as a potential novel diagnostic and therapeutic target for patients suffering from cardiomyopathy in the future.

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It has been shown that ferroptosis is involved in doxorubicin (DOX)-induced cardiotoxicity and that ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) can protect cardiomyocytes from ferroptosis. Thus, the present study aimed to investigate whether ENPP2 could protect cardiomyocytes from DOX-induced injury by inhibiting ferroptosis. H9c2 cardiomyocytes were exposed to various concentrations (0.625, 1.25, 2.5, 5 or 10 µM) of DOX for different time periods. Cell viability and ENPP2 expression were determined. ENPP2-overexpressing H9c2 cells were treated with DOX and subsequently cell viability, oxidative stress, autophagy and ferroptosis were measured using the corresponding assays (MTT assay, commercial kits and western blot analysis). Dual-luciferase reporter and chromatin immunoprecipitation assays, as well as bioinformatics analysis, were applied to detect the interaction between ENPP2 and FoxO4. Following FoxO4 overexpression in H9c2 cells, the aforementioned cellular processes were assessed. The results indicated that ENPP2 expression was downregulated following treatment of the cells with DOX. DOX also led to the decreased cell viability, reduced autophagy and elevated ferroptosis in H9c2 cells, which were notably reversed by ENPP2 overexpression. In addition, FoxO4 bound to the ENPP2 promoter, resulting in inhibition of its expression. Following FoxO4 overexpression in H9c2 cells, further experiments conducted using commercial kits and western blot analysis revealed that FoxO4 overexpression partially inhibited the effects of ENPP2 overexpression on DOX-induced oxidative stress, autophagy and ferroptosis in H9c2 cells. In conclusion, the data indicated that ENPP2 was transcriptionally regulated by FoxO4 to protect cardiomyocytes from DOX-induced toxicity by inhibiting ferroptosis. Therefore, specific treatment approaches targeting the FoxO4/ENPP2 axis and ferroptosis may provide potential therapies for alleviating DOX-induced cardiotoxicity.

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The pathogenesis of bipolar disorder (BD), a chronic mood disorder, is largely unknown. Noncoding RNAs play important roles in the pathogenesis of BD. However, little is known about the correlations of long noncoding RNAs (lncRNAs) with BD. Illumina high-throughput sequencing in BD patients and normal controls was used to identify differentially expressed (DE) genes. Two-step real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to validate DE-RNAs in the first cohort (50 BD and 50 control subjects). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and lncRNA-mRNA coexpression and lncRNA-microRNA (miRNA)-messenger RNA (mRNA) competing endogenous RNA (ceRNA) network analyses were used to predict the functions of DE-RNAs. Receiver operating characteristic (ROC) curve analysis and logistic regression were applied to evaluate diagnostic performance in an additional testing group (80 BD and 66 control subjects). A total of 576 significantly DE-lncRNAs and 262 DE-mRNAs were identified in BD patients, and 95 lncRNA-miRNA-mRNA interactions were used to construct a ceRNA regulatory network. Analysis of the first cohort showed that six RNAs (NR_028138.1, TCONS_00018621, TCONS_00002186, TNF, PID1, and SDK1) were differentially expressed in the BD group (P < 0.01). NR_028138.1 was used to establish a BD diagnostic model (area under the ROC curve 0.923, P < 0.004, 95% CI: 0.830–0.999). Verification in the second cohort revealed uniformly significant differences in NR_028138.1 (P < 0.0001). This study constructed a ceRNA regulatory network and provided a hypothesis for the pathogenesis of BD. NR_028138.1 was identified as a central element involved in the transcriptional regulation in BD and a potential biomarker.

Background This study aimed to establish and assess a prediction model for patients with persistent atrial fibrillation (AF) treated with nifekalant during the first radiofrequency catheter ablation (RFCA). Methods In this study, 244 patients with persistent AF from January 17, 2017 to December 14, 2017, formed the derivation cohort, and 205 patients with persistent AF from December 15, 2017 to October 28, 2018, constituted the validation cohort. The least absolute shrinkage and selection operator regression was used for variable screening and the multivariable Cox survival model for nomogram development. The accuracy and discriminative capability of this predictive model were assessed according to discrimination (area under the curve [AUC]) and calibration. Clinical practical value was evaluated using decision curve analysis. Results Body mass index, AF duration, sex, left atrial diameter, and the different responses after nifekalant administration were identified as AF recurrence-associated factors, all of which were selected for the nomogram. In the development and validation cohorts, the AUC for predicting 1-year AF-free survival was 0.863 (95% confidence interval (CI) 0.801–0.926) and 0.855 (95% CI 0.782–0.929), respectively. The calibration curves showed satisfactory agreement between the actual AF-free survival and the nomogram prediction in the derivation and validation cohorts. In both groups, the prognostic score enabled stratifying the patients into different AF recurrence risk groups. Conclusions This predictive nomogram can serve as a quantitative tool for estimating the 1-year AF recurrence risk for patients with persistent AF treated with nifekalant during the first RFCA.

Objectives Doxorubicin (DOX) can contribute to severe myocardial injury, and bone marrow stromal cells (BMSC)‐exosomes (Exos) improves acute myocardial infarction. Hence, this research investigated whether BMSC‐Exos alleviated DOX‐induced myocardial injury. Methods BMSC‐derived Exos were isolated and identified, and the optimal concentration of DOX was confirmed. H9C2 cells were treated with DOX and BMSC‐Exos or in combination with the protein kinase B (AKT) inhibitor. Reactive oxygen species (ROS) and JC‐1 were detected to assess oxidative stress (OS) and mitochondrial membrane damage, respectively. In addition, the expression of pyroptosis‐related molecules was measured. The expression of phosphatidylinositol 3 kinase (PI3K)‐AKT pathway‐related proteins and the phosphorylation and acetylation of forkhead box O1 (Foxo1) in the cell nucleus and cytoplasm were tested. Last, interactions between Foxo1 and gasdermin D (GSDMD) were assessed. Results BMSC‐Exo treatment increased viability and mitochondrial membrane potential and reduced lactic dehydrogenase release and ROS levels in DOX‐treated H9C2 cells. Furthermore, the addition of BMSC‐Exos suppressed DOX‐induced activation and upregulation of NLRP3 and apoptosis‐associated speck‐like protein containing A CARD (ASC) and in vitro cleavage of caspase‐1, GSDMD, interleukin (IL)‐1β, and IL‐18 proteins. Additionally, BMSC‐Exo treatment enhanced the expression of phosphorylated (p)‐PI3K, p‐AKT, and p‐mTOR in DOX‐treated H9C2 cells and the levels of phosphorylated Foxo1 in the cytoplasm of DOX‐treated H9C2 cells. Foxo1 was enriched in the promoter region of GSDMD. Moreover, the AKT inhibitor API‐2 annulled the effects of BMSC‐Exos on OS, pyroptosis, and Foxo1 phosphorylation in DOX‐treated H9C2 cells. Conclusions BMSC‐Exos phosphorylated Foxo1 and inactivated Foxo1 transcription via the PI3K‐AKT pathway to diminish GSDMD expression, thus restraining DOX‐induced pyroptosis and OS of myocardial cells.

Objective: Our study aimed to explore the mechanism network that TLR2/AP-1 combined with SOX10 to activate the MAPK pathway via CTGF in Dox-induced myocardial injury. Methods: Rats with Dox-induced myocardial injury were treated with a TLR2 inhibitor or CTGF silencing lentiviral vector. H9c2 cells were treated with genetic vectors or MAPK pathway activators. Cardiac function was tested using echocardiography and serum markers. H&E, sirius red, and TUNEL staining were used to detect myocardial pathological changes, collagen accumulation, and apoptosis. Western blot was used to detect proteins related to cardiac hypertrophy, fibrosis, apoptosis, and MAPK pathway. H9c2 cell injury was assessed by testing cell viability, LDH release, and mitochondrial membrane potential. Results: TLR2 and CTGF were highly expressed in patients with heart failure, and Dox treatment further increased their expression. Inhibiting TLR2 or silencing CTGF improved cardiac function and reduced myocardial fibrosis and apoptosis in Dox-treated rats. Silencing TLR2 alleviated Dox-induced H9c2 cell injury, which was nullified by CTGF overexpression. TLR2 activated AP-1, which cooperated with SOX10 to promote CTGF transcription. MAPK activation aggravated H9c2 cells against Dox-induced injury. Conclusions: TLR2 activates AP-1 which cooperates with SOX10 to promote CTGF transcription and subsequently activate the MAPK pathway, thereby stimulating Dox-induced myocardial injury.