Doxorubicin-induced Heart Failure Research Articles

Low-Dose Colchicine Ameliorates Doxorubicin Cardiotoxicity Via Promoting Autolysosome Degradation.

The only clinically approved drug that reduces doxorubicin cardiotoxicity is dexrazoxane, but its application is limited due to the risk of secondary malignancies. So, exploring alternative effective molecules to attenuate its cardiotoxicity is crucial. Colchicine is a safe and well-tolerated drug that helps reduce the production of reactive oxygen species. High doses of colchicine have been reported to block the fusion of autophagosomes and lysosomes in cancer cells. However, the impact of colchicine on the autophagy activity within cardiomyocytes remains inadequately elucidated. Recent studies have highlighted the beneficial effects of colchicine on patients with pericarditis, postprocedural atrial fibrillation, and coronary artery disease. It remains ambiguous how colchicine regulates autophagic flux in doxorubicin-induced heart failure. Doxorubicin was administered to establish models of heart failure both invivo and invitro. Prior studies have reported that doxorubicin impeded the breakdown of autophagic vacuoles, resulting in damaged mitochondria and the accumulation of reactive oxygen species. Following the administration of a low dose of colchicine (0.1 mg/kg, daily), significant improvements were observed in heart function (left ventricular ejection fraction: doxorubicin group versus treatment group=43.75%±3.614% versus 57.07%±2.968%, P=0.0373). In terms of mechanism, a low dose of colchicine facilitated the degradation of autolysosomes, thereby mitigating doxorubicin-induced cardiotoxicity. Our research has shown that a low dose of colchicine is pivotal in restoring the autophagy activity, thereby attenuating the cardiotoxicity induced by doxorubicin. Consequently, colchicine emerges as a promising therapeutic candidate to improve doxorubicin cardiotoxicity.

AICAR confers prophylactic cardioprotection in doxorubicin-induced heart failure in rats

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects, leading to heart failure (HF). Impaired mitochondrial function is thought to be key factor driving progression into HF. We have previously shown in a rat model of DOX-HF that heart failure with reduced ejection fraction correlates with mitochondrial loss and dysfunction. Adenosine monophosphate-dependent kinase (AMPK) is a cellular energy sensor, regulating mitochondrial biogenesis and energy metabolism, including fatty acid oxidation. We hypothesised that AMPK activation could restore mitochondrial function and therefore be a novel cardioprotective strategy for the prevention of DOX-HF. Consequently, we set out to assess whether 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR), an activator of AMPK, could prevent cardiac functional decline in this chronic intravenous rat model of DOX-HF. In line with our hypothesis, AICAR improved cardiac systolic function. AICAR furthermore improved cardiac mitochondrial fatty acid oxidation, independent of mitochondrial number, and in the absence of observable AMPK-activation. In addition, we found that AICAR prevented loss of myocardial mass. RNAseq analysis showed that this may be driven by normalisation of pathways associated with ribosome function and protein synthesis, which are impaired in DOX-treated rat hearts. AICAR furthermore prevented dyslipidemia and excessive body-weight loss in DOX-treated rats, which may contribute to preservation of myocardial mass. Though it is unclear whether AICAR exerted its cardioprotective effect through cardiac or extra-cardiac AMPK-activation or via an AMPK-independent effect, these results show promise for the use of AICAR as a cardioprotective agent in DOX-HF to both preserve cardiac function and mass.

NADPH oxidase 2 mediates cardiac sympathetic denervation and myocyte autophagy, resulting in cardiac atrophy and dysfunction in doxorubicin-induced cardiomyopathy

Doxorubicin has been used extensively as a potent anticancer agent, but its clinical use is limited by its cardiotoxicity. However, the underlying mechanisms remain to be fully elucidated. In this study, we tested whether NADPH oxidase 2 (Nox2) mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy, resulting in cardiac atrophy and dysfunction in doxorubicin-induced heart failure. Nox2 knockout (KO) and wild-type (WT) mice were randomly assigned to receive a single injection of doxorubicin (15 mg/kg, i.p.) or saline. WT doxorubicin mice exhibited the decreases in survival rate, left ventricular (LV) wall thickness and LV fractional shortening and the increase in the lung wet-to-dry weight ratio 1 week after the injections. These alterations were attenuated in Nox2 KO doxorubicin mice. In WT doxorubicin mice, myocardial oxidative stress was increased, myocardial noradrenergic nerve fibers were reduced, myocardial expression of PGP9.5, GAP43, tyrosine hydroxylase and norepinephrine transporter was decreased, and these changes were prevented in Nox2 KO doxorubicin mice. Myocyte autophagy was increased and myocyte size was decreased in WT doxorubicin mice, but not in Nox2 KO doxorubicin mice. Nox2 mediates cardiac sympathetic nerve terminal abnormalities and myocyte autophagy—both of which contribute to cardiac atrophy and failure after doxorubicin treatment.

The m6A demethylase fat mass and obesity-associated protein mitigates pyroptosis and inflammation in doxorubicin-induced heart failure via the toll-like receptor 4/NF-κB pathway.

Doxorubicin (Dox) can induce cardiotoxicity, thereby restricting the utility of this potent drug. Herein, the study ascertained the mechanism of the N6-methyladenosine (m6A) demethylase fat mass and obesity-associated protein (FTO) in pyroptosis and inflammation during Dox-induced heart failure (HF). Serum samples were collected from HF patients for detection of the expression of FTO and toll-like receptor 4 (TLR4). Dox-treated H9C2 cardiomyocytes were chosen for in vitro HF modeling, followed by measurement of FTO and TLR4 expression. Cardiomyocytes were detected for viability, apoptosis, spatial distribution of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), and the levels of lactic dehydrogenase, inflammatory factors, oxidative stress markers, and pyroptosis-related proteins. The m6A levels of mRNA were examined. RNA immunoprecipitation (RIP) and mRNA stability measurement were used to determine mRNA and protein expression, and RNA m6A dot blot and methylated-RIP assay were performed to detect m6A methylation levels. The expression of p-NF-κB p65 and p-IκB-α was measured by western blotting. In the serum of HF patients, FTO was elevated while TLR4 was decreased. Dox treatment reduced FTO expression and increased m6A methylation levels and TLR4 expression in H9C2 cells. Overexpression of FTO and knockdown of TLR4 reduced apoptosis, cytotoxicity, inflammation, pyroptosis, oxidative stress, NLRP3 co-localization, and fluorescence intensity in Dox-induced H9C2 cells. Mechanistically, FTO resulted in reduced binding activity of YTHDF1 to TLR4 mRNA via m6A demethylation of TLR4, thus declining TLR4, p-NF-κB p65, and p-IκB-α expression. TLR4 knockdown counteracted the effects of FTO knockdown on Dox-induced H9C2 cells. FTO alleviated Dox-induced HF by blocking the TLR4/NF-κB pathway.

Current Research Status and Implication for Further Study of Real-World Data on East Asian Traditional Medicine for Heart Failure: A Scoping Review.

This study used real-world data (RWD) to explore the long-term effects of East Asian traditional medicine (EATM) on heart failure (HF). A comprehensive search was conducted across five databases to identify relevant studies, which were then reviewed using the Arksey and O'Malley scoping review framework. The analysis focused on a descriptive examination of the long-term outcomes associated with EATM intervention. Methodologically, the study explored various aspects, including study subjects, interventions, applied clinical outcomes, and statistical methods. Out of 258 studies, 12 were selected. Eight studies involved patients with HF, while the others used HF as an outcome. Datasets from the National Health Insurance Research Database were used in Taiwan, while electronic medical record data were used in China and Japan. EATM interventions have been found to be associated with lower mortality and readmission rates. One study indicated that an increased dose of Fuzi, a botanical drug, or prompt use of Fuzi after diagnosis led to a decreased mortality hazard ratio. In two studies examining readmission rates, a significant increase was observed in the non-exposed group, with odds ratios of 1.28 and 1.18. Additionally, in patients with breast cancer, the subdistribution hazard ratio for the occurrence of doxorubicin-induced HF was reduced to 0.69. Although cohort studies with survival analysis were common, methodological flaws, such as issues with statistical methods and HF diagnosis, were identified. Despite these challenges, the study observed an association between EATM and improved clinical outcomes in patients with HF, emphasizing the potential of RWD studies to complement randomized controlled trials, especially for longer-term follow-ups. These results provide foundational data for future RWD research.

Targeting heat shock protein 47 alleviated doxorubicin-induced cardiotoxicity and remodeling in mice through suppression of the NLRP3 inflammasome

AimDoxorubicin-induced cardiotoxicity (DIC) is an increasing problem, occurring in many cancer patients receiving anthracycline chemotherapy, ultimately leading to heart failure (HF). Unfortunately, DIC remains difficult to manage due to an ignorance regarding pathophysiological mechanisms. Our work aimed to evaluate the role of HSP47 in doxorubicin-induced HF, and to explore the molecular mechanisms. Methods and resultsMice were exposed to multi-intraperitoneal injection of doxorubicin (DOX, 4mg/kg/week, for 6 weeks continuously) to produce DIC. HSP47 expression was significantly upregulated in serum and in heart tissue in DOX-treated mice and in isolated cardiomyocytes. Mice with cardiac-specific HSP47 overexpression and knockdown were generated using recombinant adeno-associated virus (rAVV9) injection. Importantly, cardiac-specific HSP47 overexpression exacerbated cardiac dysfunction in DIC, while HSP47 knockdown prevented DOX-induced cardiac dysfunction, cardiac atrophy and fibrosis in vivo and in vitro. Mechanistically, we identified that HSP47 directly interacted with IRE1α in cardiomyocytes. Furthermore, we provided powerful evidence that HSP47-IRE1α complex promoted TXNIP/NLRP3 inflammasome and reinforced USP1-mediated NLRP3 ubiquitination. Moreover, NLRP3 deficiency in vivo conspicuously abolished HSP47-mediated cardiac atrophy and fibrogenesis under DOX condition. ConclusionHSP47 was highly expressed in serum and cardiac tissue after doxorubicin administration. HSP47 contributed to long-term anthracycline chemotherapy-associated cardiac dysfunction in an NLRP3-dependent manner. HSP47 therefore represents a plausible target for future therapy of doxorubicin-induced HF.

Melatonin attenuates an impairment of metabolic reprogramming in doxorubicin-induced cardiotoxicity: insights from metabolomics study in rats

Abstract Background Doxorubicin is an effective chemotherapeutic agent. Unfortunately, the clinical utilization of doxorubicin is limited due to cardiotoxicity. It was previously shown that doxorubicin caused the changes in glycolysis metabolome levels, fatty acid levels, and genes involving lipid metabolism in the heart. However, the pattern of metabolic reprogramming in doxorubicin-induced heart failure remains unknown. Moreover, the benefit of melatonin in attenuating doxorubicin-induced heart failure was previously revealed. Nonetheless, the potential benefits of melatonin on metabolic reprogramming in doxorubicin-induced heart failure has never been determined. Purposes Using liquid chromatography coupled with mass spectrometry-based targeted metabolomics, we identified the pattern of metabolic reprogramming in rats with doxorubicin-induced heart failure. In addition, the effects of melatonin on metabolic reprogramming in doxorubicin-induced heart failure were investigated. Methods Male Wistar rats (n=18) were divided into 3 groups (n=6/group) to receive either 1) normal saline solution as a vehicle, 2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29, and 3) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 plus 10 mg/kg/day of melatonin at days 0-29. At day 30, echocardiography and heart rate variability were done for an evaluation of cardiac function. The rats were then euthanized to collect ventricular cardiac tissues for metabolomics study. Results Comparing to vehicle-treated rats, the heart of rats treated with doxorubicin alone exhibited cardiac dysfunction, increased glucose and ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased adenosine triphosphate (ATP) production. The co-treatment with melatonin effectively restored cardiac function, glucose and ketone body utilization, and ATP production in the heart. Interestingly, the co-treatment with melatonin also increased cardiac fatty acid oxidation, branched-chain amino acid catabolism, and anaplerosis (Figure). Conclusions Our findings highlighted the potential benefits of melatonin on cardiac metabolic reprogramming impaired by doxorubicin. These findings also suggested that melatonin could be considered as an adjunctive treatment for doxorubicin-induced heart failure in clinical settings.

Abstract 15504: Impaired Branched-Chain Amino Acid Catabolism is Associated With Chemotherapy-Induced Heart Failure and Rescued by Metformin

Introduction: Heart failure resulting from cancer therapies represents a major cause of morbidity in cancer survivors. Interventional strategies to prevent and treat heart dysfunction in cardio-oncology patients continue to remain a challenge. Hypothesis: We posit that Branched-Chain Amino Acid Catabolism (BCAA) catabolism dysfunction is a likely causal mechanistic pathway in the pathogenesis of CTHF. Methods: In this study, we leveraged electronic health records , human-induced pluripotent stem cell ( iPSC )-derived cardiomyocyte model-based mechanistic studies, murine models, and network medicine-basedtranscriptomics analytic methodologies, to suggest that rescuing BCAA catabolic dysfunction is a promising approach for managing chemotherapy-induced heart failure, using doxorubicin as a prototypical example. Results: In our large-scale cardio-oncology cohort, we observed a significant incidence of heart dysfunction and abnormal NT-proBNP levels among patients treated with doxorubicin. Using murine heart failure models, we identified significant correlations between the abundance of branched-chain amino acids (isoleucine, leucine, and valine) and cardiac dysfunction after doxorubicin exposure. Mechanistic observations in human-induced pluripotent stem cell (iPSC)-derived cardiomyocyte models further support impaired branched-chain amino acid (BCAA) catabolism by doxorubicin. Through metabolite-enzyme network analysis, we identified metformin as a repurposable drug capable of restoring branched-chain amino acid catabolism, thereby improving mitochondrial function. Human iPSC-based mechanistic studies revealed that metformin combined with doxorubicin resulted in improved insulin signaling, endothelial cell reprogramming, increased RARA gene expression (a key doxorubicin-induced heart failure GWAS gene) and reduced pro-fibrotic signaling. Furthermore, we demonstrate that metformin improved murine cardiac function following doxorubicin exposure. Conclusions: Our findings utilized electronic health records, iPSC-based mechanistic studies, and murine models to suggest that BCAA catabolic dysfunction may be a promising approach for managing chemotherapy-induced heart failure.

Integrating Network Pharmacology and an Experimental Model to Investigate the Effect of Zhenwu Decoction on Doxorubicin-Induced Heart Failure.

Doxorubicin-induced heart failure is a clinical problem that needs to be solved urgently. Previous studies have confirmed that Zhenwu Decoction, a traditional Chinese medicine compound, can effectively improve chronic heart failure. However, its interventional effect on Doxorubicin-induced heart failure has not yet been investigated. In this study, we investigated the therapeutic effect and potential mechanism of Zhenwu Decoction on Doxorubicin-induced heart failure through animal experiments and network pharmacology. The study aimed to investigate the therapeutic effect and potential mechanism of Zhenwu Decoction (ZWD) on Doxorubicin-induced heart failure. A heart-failure mouse model was established in 8-week-old male C57/BL6J mice using Doxorubicin, and the mice were then treated with ZWD for a 4-week period. Firstly, network pharmacology was conducted to explore the potential active components and molecular mechanisms of ZWD on Doxorubicin-induced heart failure. Next, we conducted an in vivo study on the effect of ZWD on Doxorubicin-induced heart failure. After the intervention, the cardiac function and levels of cardiac function injury marker in serum were measured to evaluate the therapeutic effect of ZWD on cardiac function. Then HE staining and Masson staining were used to evaluate the effect of ZWD on myocardial pathology, and biochemical method was used to detect the effect of ZWD on total antioxidant capacity and inflammation, and finally, Western blot was used to detect TGFβ, Smad-3, and collagen I protein expression levels to evaluate its effect on myocardial fibrosis. In Doxorubicin-induced heart failure mice, ZWD improved cardiac function and reduced the levels of CK-MB, NT-proBNP, and BNP in the serum, improved myocardial pathology, and reduced TGFβ, Smad-3 and collagen I protein expression levels to improve myocardial fibrosis. Network pharmacological analysis showed that ZWD has 146 active ingredients and 248 candidate targets. Moreover, 2,809 genes were found to be related to Doxorubicin-induced heart failure, and after screening, 74 common targets were obtained, mainly including IL-6, AKT1, caspase-3, PPARG, PTGS2, JUN, HSP90AA1, and ESR1. KEGG analysis confirmed that PI3K/AKT and IL-6/NF-κB signaling pathways were the two main pathways underlying the cardioprotective effects of ZWD. Finally, in vivo experiments showed that ZWD improved the total antioxidant capacity, reduced the SOD level, increased the protein expression of PI3K, Akt, Bcl-2, Bax, and caspase-3, reduced the levels of TNF-α, IL-6, and IL-1β, and decreased the NF-κB p65, IL-6, and TNF-α protein expression levels. In Doxorubicin-induced heart-failure mice, Zhenwu Decoction improved the cardiac function and myocardial pathology, and improved myocardial fibrosis through the TGFβ/Smad-3 signaling pathway. According to the prediction of network pharmacology, in vivo experiments demonstrated that Zhenwu Decoction can improve the oxidative stress response, improve myocardial cell apoptosis through the PI3K/AKT signaling pathway, and improve myocardial inflammation by reducing the levels of inflammatory factors and by reducing the protein expression of NF-κB p65, IL-6, and TNF-α.

Sanwei sandalwood decoction improves function of the gut microbiota in heart failure.

To investigate the effects of Sanwei sandalwood decoction on improving function of the intestinal flora in doxorubicin-induced heart failure in rats. Thirty Sprague-Dawley rats were screened and randomly assigned into a blank group, a model group, and a Sanwei sandalwood decoction group (treatment group). The rat model of heart failure was prepared and established in the latter two groups. After successful model establishment, the treatment group received Sanwei sandalwood decoction by continuous gavage at 2 g/kg, once daily for 4 weeks. The other groups were given an equivalent volume of saline. After the final dose, fecal samples were collected from each group and analyzed by macrogenomics and nontargeted metabolomics to characterize the intestinal flora and associated metabolites. The composition of gut microbiota was significantly different between the three groups. There were 778,808 common genes between the blank and model groups, while 49,315 genes were lost and 521,008 were gained in the model group relative to the blank group. At the phylum level, all groups of rat fecal samples were dominated by Firmicutes, Bacteroidota, Actinobacteria, and Proteobacteria. At the genus level, the microbial community composition in all experimental groups of rat fecal samples was dominated by Lactobacillus, Bifidobacterium, Limosilactobacillus, Allobaculum, Prevotella, and Ligilactobacillus spp. Interestingly, cluster analysis was performed on the top 30 KEGG ontology (KO) terms displaying significant differences in relative abundance in the rat fecal microbiome among experimental groups. The relative frequency of posttranslational modification, coenzyme transport and metabolism, cell wall, membrane, and envelope biogenesis in the eggNOG and CAZy databases. In the nontargeted metabolomics, the group principal component analysis revealed that the groups were well distinguished from one another. The different metabolites were screened with VIP >1, and the KEGG different metabolite classification and enrichment analysis revealed that there includes 15 metabolites pathway, including loxoprofen, conifery-l-acetate, trichilin A, and others. The arachidonic acid pathway also accounted for a significant portion of the KEGG pathway classification analysis. Sanwei sandalwood decoction positively affects the intestinal microbial environment of rats with heart failure, improving the gut dysbiosis that is caused by the condition. This treatment intervention inhibits the growth of pathogenic bacteria and promotes the growth of beneficial species.

Exploration of Key Immune-Related Transcriptomes Associated with Doxorubicin-Induced Cardiotoxicity in Patients with Breast Cancer

Based on a few studies, heart failure patients with breast cancer were assessed to find potential biomarkers for doxorubicin-induced cardiotoxicity. However, key immune-related transcriptional markers linked to doxorubicin-induced cardiotoxicity in breast cancer patients have not been thoroughly investigated. We used GSE40447, GSE76314, and TCGA BRCA cohorts to perform this study. Then, we performed various bioinformatics approaches to identify the key immune-related transcriptional markers and their association with doxorubicin-induced cardiotoxicity in patients with breast cancer. We found 255 upregulated genes and 286 downregulated genes in patients with doxorubicin-induced heart failure in breast cancer. We discovered that in patients with breast cancer comorbidity doxorubicin-induced cardiotoxicity, the 58 immunological genes are elevated (such as CPA3, VSIG4, GATA2, RFX2, IL3RA, and LRP1), and the 60 genes are significantly suppressed (such as MS4A1, FCRL1, CD200, FCRLA, FCRL2, and CD79A). Furthermore, we revealed that the immune-related differentially expressed genes (DEGs) are substantially associated with the enrichment of KEGG pathways, including B-cell receptor signaling pathway, primary immunodeficiency, chemokine signaling pathway, hematopoietic cell lineage, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, MAPK signaling pathway, focal adhesion, dilated cardiomyopathy, cell adhesion molecule, etc. Moreover, we discovered that the doxorubicin-induced immune-related genes are crucially involved in the protein–protein interaction and gene clusters. The immune-related genes, including IFIT5, XCL1, SPIB, BTLA, MS4A1, CD19, TCL1A, CD83, CD200, FCRLA, CD79A, BIRC3, and IGF2R are significantly associated with a poor survival prognosis of breast cancer patients and showed diagnostic efficacy in patients with breast cancer and heart failure. Molecular docking revealed that the survival-associated genes interact with the doxorubicin with appreciable binding affinity. Finally, we validated the expression level of immune-related genes in breast cancer patients-derived cardiomyocytes with doxorubicin-induced cardiotoxicity and found that the level of RAD9A, HSPA1B, GATA2, IGF2R, CD200, ERCC8, and BCL11A genes are consistently dysregulated. Our findings offered a basis for understanding the mechanism and pathogenesis of the cardiotoxicity caused by doxorubicin in breast cancer patients and predicted the interaction of immune-related potential biomarkers with doxorubicin.

Dioscin ameliorates doxorubicin-induced heart failure via inhibiting autophagy and apoptosis by controlling the PDK1-mediated Akt/mTOR signaling pathway.

Heart failure (HF) is a disease with high mortality and morbidity rate. Autophagy is critically implicated in HF progression. The current research was designed to investigate the function of Dioscin on oxidative stress, autophagy, and apoptosis in HF. In this study, doxorubicin (Dox) was employed to induce HF model and HL-1 cell damage model. Echocardiography implied that Dioscin could dramatically relieve heart function in vivo. Western blotting determined that Dioscin treatment reversed the promotive effect of autophagy caused by Dox through modulating levels of key autophagy-associated molecules, including Atg5 and Beclin1. Dioscin also impaired apoptosis by regulating apoptosis-related protein, including Bcl-2 and cleaved caspase-3 following Dox treatment in vivo and in vitro. Furthermore, the impacts of Dioscin were mediated by upregulation of PDK1-mediated Akt/mTOR signaling. The mTOR inhibitor (rapamycin) could counteract the therapeutic impact of Dioscin in vitro. Taken together, Dioscin could relieve cardiac function through blocking apoptosis and autophagy by activating the PDK1-elicited Akt/mTOR pathway.

Effects of melatonin on cardiac metabolic reprogramming in doxorubicin-induced heart failure rats: A metabolomics study for potential therapeutic targets.

Using mass spectrometry-based targeted metabolomics, we aimed to determine the pattern of cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. More importantly, we aimed to identify the potential effects of melatonin on cardiac metabolic reprogramming and energetics in doxorubicin-induced heart failure. Male Wistar rats (n = 18) were randomly divided into three groups (n = 6/group) to receive either (1) normal saline solution as a control, (2) 3 mg/kg/day of doxorubicin on Days 0, 4, 8, 15, 22, and 29, or (3) 3 mg/kg/day of doxorubicin on Days 0, 4, 8, 15, 22, and 29 plus 10 mg/kg/day of melatonin on Days 0-29. On Day 30, echocardiography was carried out and heart rate variability was analyzed for the evaluation of cardiac function. The rats were euthanized on the following day to enable the collection of ventricular cardiac tissue. Compared to the control group, the hearts of rats treated with doxorubicin alone exhibited impaired cardiac function, increased glucose and ketone body utilization, decreased fat utilization, decreased succinate oxidation, and decreased production of adenosine triphosphate. The cotreatment with melatonin could restore cardiac function, glucose and ketone body utilization, and adenosine triphosphate production in the heart. Interestingly, the cotreatment with melatonin led to an increase in cardiac fatty acid oxidation, branched-chain amino acid catabolism, and anaplerosis. All of these findings highlighted the potential efficacy of melatonin with regard to cardiac metabolic reprogramming and energetics. Our findings also suggested that melatonin could be considered as an adjunctive treatment for doxorubicin-induced heart failure in clinical practice.

Changes in the gut microbiota structure and function in rats with doxorubicin-induced heart failure.

The rat model of heart failure (HF) induced by doxorubicin (DOX), a broad spectrum and highly effective chemotherapeutic anthracycline with high-affinity to myocardial tissue that causes severe dose-dependent irreversible cardiotoxicity has been widely recognized and applied in HF pathogenesis and drug therapy studies. The gut microbiota (GM) has attracted significant attention due to its potential role in HF, and research in this area may provide beneficial therapeutic strategies for HF. Considering the differences in the route, mode, and total cumulative dose of DOX administration used to establish HF models, the optimal scheme for studying the correlation between GM and HF pathogenesis remains to be determined. Therefore, focusing on establishing the optimal scheme, we evaluated the correlation between GM composition/function and DOX-induced cardiotoxicity (DIC). Three schemes were investigated: DOX (at total cumulative doses of 12, 15 or 18 mg/kg using a fixed or alternating dose via a tail vein or intraperitoneal injection) was administered to Sprague Dawley (SD) for six consecutive weeks. The M-mode echocardiograms performed cardiac function evaluation. Pathological changes in the intestine were observed by H&E staining and in the heart by Masson staining. The serum levels of N-terminal pre-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) were measured by ELISA. The GM was analysed by 16S rRNA gene sequencing. Strikingly, based on the severity of cardiac dysfunction, there were marked differences in the abundance and grouping of GM under different schemes. The HF model established by tail vein injection of DOX (18 mg/kg, alternating doses) was more stable; moreover, the degree of myocardial injury and microbial composition were more consistent with the clinical manifestations of HF. The model of HF established by tail vein injection of doxorubicin, administered at 4mg/kg body weight (2mL/kg) at weeks 1, 3 and 5, and at 2mg/kg body weight (1mL/kg) at weeks 2, 4 and 6, with a cumulative total dose of 18mg/kg, is a better protocol to study the correlation between HF and GM.

THE ANTIOXIDANT PROTECTION SYSTEM STATE OF RATS UNDER EXPERIMENTAL DOXORUBICIN INTOXICATION AND THE EFFECTS OF CORRECTING FACTORS

Introduction. The doxorubicin model was used for research, which, according to many authors, most adequately reproduces heart failure of varying degrees of severity. Doxorubicin is an antibiotic that has a cytostatic effect. The mechanism of its action consists of interaction with DNA, formation of free radicals, and inhibition of nucleic acid synthesis. The doxorubicin action and the development of hypoxia are accompanied by the activation of oxidative stress, the strengthening of free radical processes, and changes in the metabolism of carbohydrates, proteins, and lipids.
 The aim of the study – the effect of the drug “Bendamine” on the indicators of antioxidant protection of the body of rats under experimental simulation of heart failure.
 Research Methods. Modeling of heart failure was performed on sexually mature male Wistar rats with a body weight of 180–200 g. In blood and myocardial homogenate, the level of lipid peroxidation products, the activity of antioxidant enzymes, and the level of reduced glutathione were determined against the background of doxorubicin intoxication and when using the drug “Bendamine”.
 Results and Discussion. During doxorubicin intoxication, LPO processes are enhanced in rats, which is indicated by the increased lipid hydroperoxides, diene conjugates, and TBA-active products in the blood and the homogenate of the rat myocardium of the first experimental group. It is worth noting that the inhibition of the antioxidant defense system was also established in intoxicated rats, as indicated by the low level of both enzymatic and non-enzymatic links of the antioxidant system. It was established that bendamine has a corrective effect on rats' oxidative stress conditions inherent in doxorubicin-induced heart failure. The drug “Bendamine” inhibits the excessive formation of POL products in pathologically changed tissues of the heart of rats and has an inducing effect on the system of antioxidant protection.
 Conclusions. The influence of the drug "Bendamine" on the indicators of antioxidant protection of the body of rats under experimental simulation of heart failure was studied. Its antioxidant properties have been proven.
 
  

Angiotensin II type 2 receptor agonist treatment of doxorubicin induced heart failure

ABSTRACT Doxorubicin (DOX) is an anthracycline derivative used for treatment of malignancies; however, its clinical use is limited by its cardiotoxicity. We investigated the effects of angiotensin II type 2 receptor agonist compound 21 (C21) on DOX induced heart failure in rat heart. We compared C21 with losartan (LOS), an AT 1 receptor antagonist used for treating heart failure. We allocated 40 rats into five groups of eight: saline treated control group, DOX group administered a single 20 mg/kg dose of DOX, DOX + C21 group administered 0.3 mg/kg C21 for 21 days following the 20 mg/kg dose of DOX, DOX + losartan (LOS) group administered a 21 day regimen of 20 mg/kg LOS following the single dose of DOX, and a DOX + LOS + C21 group administered 0.3 mg/kg C21 and 20 mg/kg LOS for 21 days following the single dose of DOX. We assessed histopathology and conducted echocardiograpic and hemodynamic measurements. Left ventricular ejection fraction (EF) was reduced only in the DOX treated group. C21, LOS and C21 + LOS therapy prevented decreased EF due to DOX. Less histopathology was observed in the DOX + LOS + C21 group than for the other treatment groups. Application of C21 decreased DOX induced cardiac injury similar to LOS. Combined use of C21 and LOS was most beneficial for DOX induced heart failure.

Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Fasting strategies are under active clinical investigation in patients receiving chemotherapy. Prior murine studies suggest that alternate-day fasting may attenuate doxorubicin cardiotoxicity and stimulate nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. In this study, human heart tissue from patients with doxorubicin-induced heart failure demonstrated increased nuclear TFEB protein. In mice treated with doxorubicin, alternate-day fasting or viral TFEB transduction increased mortality and impaired cardiac function. Mice randomized to alternate-day fasting plus doxorubicin exhibited increased TFEB nuclear translocation in the myocardium. When combined with doxorubicin, cardiomyocyte-specific TFEB overexpression provoked cardiac remodeling, while systemic TFEB overexpression increased growth differentiation factor 15 (GDF15) and caused heart failure and death. Cardiomyocyte TFEB knockout attenuated doxorubicin cardiotoxicity, while recombinant GDF15 was sufficient to cause cardiac atrophy. Our studies identify that both sustained alternate-day fasting and a TFEB/GDF15 pathway exacerbate doxorubicin cardiotoxicity.

Delivery of mitochondria confers cardioprotection through mitochondria replenishment and metabolic compliance

Mitochondrial dysfunction is a hallmark of heart failure. Mitochondrial transplantation has been demonstrated to be able to restore heart function, but its mechanism of action remains unresolved. Using an in-house optimized mitochondrial isolation method, we tested efficacy of mitochondria transplantation in two different heart failure models. First, using a doxorubicin-induced heart failure model, we demonstrate that mitochondrial transplantation before doxorubicin challenge protects cardiac function invivo and prevents myocardial apoptosis, but contraction improvement relies on the metabolic compatibility between transplanted mitochondria and treated cardiomyocytes. Second, using a mutation-driven dilated cardiomyopathic human induced pluripotent stem cell-derived cardiomyocyte model, we demonstrate that mitochondrial transplantation preferentially boosts contraction in the ventricular myocytes. Last, using single-cell RNA-seq, we show that mitochondria transplantation boosts contractility in dystrophic cardiomyocytes with few transcriptomic alterations. Together, we provide evidence that mitochondria transplantation confers myocardial protection and may serve as a potential therapeutic option for heart failure.

GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis in doxorubicin-induced heart failure through inhibition of NADPH oxidase-derived oxidative stress

Doxorubicin (DOX), which is widely used for the treatment of cancer, induces cardiomyopathy associated with NADPH oxidase-derived reactive oxygen species. GSK2795039 is a novel small molecular NADPH oxidase 2 (Nox2) inhibitor. In this study, we investigated whether GSK2795039 prevents receptor-interacting protein kinase 1 (RIP1)-RIP3-mixed lineage kinase domain-like protein (MLKL)-mediated cardiomyocyte necroptosis in DOX-induced heart failure through NADPH oxidase inhibition. Eight-week old mice were randomly divided into 4 groups: control, GSK2795039, DOX and DOX plus GSK2795039. H9C2 cardiomyocytes were treated with DOX and GSK2795039. In DOX-treated mice, the survival rate was reduced, left ventricular (LV) end-systolic dimension was increased and LV fractional shortening was decreased, and these alterations were attenuated by the GSK2795039 treatment. GSK2795039 inhibited not only myocardial NADPH oxidase subunit gp91phox (Nox2) protein, but also p22phox, p47phox and p67phox proteins and prevented oxidative stress 8-hydroxy-2′-deoxyguanosine levels in DOX-treated mice. RIP3 protein and phosphorylated RIP1 (p-RIP1), p-RIP3 and p-MLKL proteins, reflective of their respective kinase activities, markers of necroptosis, were markedly increased in DOX-treated mice, and the increases were prevented by GSK2795039. GSK2795039 prevented the increases in serum lactate dehydrogenase and myocardial fibrosis in DOX-treated mice. Similarly, in DOX-treated cardiomyocytes, GSK2795039 improved cell viability, attenuated apoptosis and necrosis and prevented the increases in p-RIP1, p-RIP3 and p-MLKL expression. In conclusion, GSK2795039 prevents RIP1-RIP3-MLKL-mediated cardiomyocyte necroptosis through inhibition of NADPH oxidase-derived oxidative stress, leading to the improvement of myocardial remodeling and function in DOX-induced heart failure. These findings suggest that GSK2795039 may have implications for the treatment of DOX-induced cardiomyopathy.

Oxidative Stress and Pyroptosis in Doxorubicin-Induced Heart Failure and Atrial Fibrillation.

Patients undergoing doxorubicin (Dox) chemotherapy often develop new-onset atrial fibrillation and heart failure. Recent studies indicate that the TLR4/MyD88/NLRP3 pyroptosis signaling pathway plays a key role in the occurrence and development of cancer, heart failure, and atherosclerosis. However, few studies investigated the role of oxidative stress and pyroptosis in doxorubicin-induced heart failure and new-onset atrial fibrillation. In this study, we recruited 84 healthy subjects, 112 patients undergoing Dox chemotherapy showing heart failure (HF), and 62 patients undergoing Dox treatment who manifested atrial fibrillation (AF). The mRNA and protein levels of TLR4 expression, several downstream pyroptosis-associated proteins (cleaved caspase-1, NLRP3, GSDMD-N, and HMGB-1), serum inflammatory factors, and oxidative stress were detected at the beginning of chemotherapy and after 3 months of Dox chemotherapy. Oxidative stress and downstream pyroptosis-associated proteins tended to increase in the Dox-baseline group to the Dox-HF group. However, virtually no change in the expression of either oxidative stress or pyroptosis-associated proteins was detected in patients after three months of Dox chemotherapy compared with those at baseline. This study suggests that the prolonged oxidative stress and high levels of pyroptosis-associated proteins contribute to cardiac systolic dysfunction, suggesting TLR4 as a novel biomarker and a potential treatment target for doxorubicin-induced heart failure.