Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity
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PROVIDER: S-EPMC10070098 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Project description:Doxorubicin (DOX), a chemotherapeutic agent, induces a cardiotoxicity referred to as doxorubicin-induced cardiomyopathy (DIC). This cardiotoxicity often limits chemotherapy for malignancies and is associated with poor prognosis. However, the molecular mechanism underlying this cardiotoxicity is yet to be fully elucidated. Here, we show that DOX downregulated glutathione peroxidase 4 (GPx4) and induced excessive lipid peroxidation through DOX-Fe2+ complex in mitochondria, leading to mitochondria-dependent ferroptosis; we also show that mitochondria-dependent ferroptosis is a major cause of DOX cardiotoxicity. In DIC mice, the left ventricular ejection fraction was significantly impaired, and fibrosis and TUNEL+ cells were induced at day 14. Additionally, GPx4, an endogenous regulator of ferroptosis, was downregulated, accompanied by the accumulation of lipid peroxides, especially in mitochondria. These cardiac impairments were ameliorated in GPx4 Tg mice and exacerbated in GPx4 heterodeletion mice. In cultured cardiomyocytes, GPx4 overexpression or iron chelation targeting Fe2+ in mitochondria prevented DOX-induced ferroptosis, demonstrating that DOX triggered ferroptosis in mitochondria. Furthermore, concomitant inhibition of ferroptosis and apoptosis with ferrostatin-1 and zVAD-FMK fully prevented DOX-induced cardiomyocyte death. Our findings suggest that mitochondria-dependent ferroptosis plays a key role in progression of DIC and that ferroptosis is the major form of regulated cell death in DOX cardiotoxicity.
| S-EPMC7253028 | biostudies-literature
Project description:BackgroundThe severe unfavorable effects of doxorubicin on the heart restrict its clinical usage. Numerous investigations document that cyclic GMP-AMP synthase (cGAS) activator of interferon genes (STING) cascade influences inflammation along with the immune response in a variety of diseases. The pathophysiological function of the cGAS-STING cascade in Doxorubicin-induced cardiomyopathy (DIC) is, nevertheless, unknown.MethodsIn vivo, cardiotoxicity was triggered by a single dose of intra-peritoneal inoculation of doxorubicin (15 mg/kg) in wild-type C57BL/6J mice and STING knockdown animals. Adeno-associated virus 9 (AAV9) was utilized to silence STING. qPCR along with Western blotting were adopted to assess alterations in the cGAS/STING cascade. To assess cardiac function, we employed echocardiography coupled with histology, as well as molecular phenotyping. In vitro, HL-1 cardiomyocytes were introduced as test models.ResultsIn wild type mice, doxorubicin stimulation significantly activated the cGAS/STING pathway. STING silencing increased rate of survival along with heart function in mice, as well as diminished myocardial inflammatory cytokines along with apoptosis. These observations were also confirmed by utilizing siRNA of STING in vitro studies.ConclusionThis research premise established that STING inhibition could alleviate Dox-triggered cardiotoxicity in mice. As a result, preventing DIC by repressing STING in cardiomyocytes might be a possible treatment approach.
| S-EPMC10037834 | biostudies-literature
Project description:Cluh is a cytosolic protein that is known to specifically bind the mRNAs of nuclear-encoded mitochondrial proteins and play critical roles in mitochondrial biogenesis. Here, we report the role of Cluh in adipogenesis. Our study shows that mRNA expression of Cluh is stimulated during adipogenesis, and that cAMP/Creb signalling increases its transcription. Cluh depletion impaired proper adipocyte differentiation, with reductions seen in lipid droplets and adipogenic marker gene expression. Interestingly, the inductions of the brown adipocyte-specific genes, Ucp1, Cidea and Cox7a1, are severely blocked by Cluh depletion during brown adipogenesis. Mitochondrial respiration and the stability of mRNAs encoding mitochondrial proteins are reduced by Cluh depletion during brown adipogenesis. These results suggest that Cluh, which is induced during adipogenesis, promotes the post-transcriptional regulation of mitochondrial proteins and supports differentiation.
| S-EPMC6497719 | biostudies-literature
Project description:Doxorubicin (DOX), a chemotherapeutic drug widely used in the clinical setting, is known to cause serious cardiotoxicity and greatly reduces the survival rate as well as quality of life of patients receiving chemotherapy. Peroxisome proliferation activated receptor α (PPARα) is a type of ligand activated receptor of the nuclear hormone receptor family that regulates multiple gene expression. Several studies have shown that PPARα has anti-apoptotic and cardio-protective effects. However, its role in DOX-induced cardiotoxicity is rarely reported. In this study, we observed decreased expression of PPARα in the heart of tumor-bearing mice already treated with DOX; however, no such phenomenon was observed in tumor tissues. Next, we observed that the PPARα agonist, fenofibrate (FENO), had no effect on tumor progression; however, it enhanced cardiac function in tumor-bearing mice treated with DOX. Subsequently, recombinant adeno-associated virus serotype 9 (rAAV9) was used to manipulate the expression of PPARα in the heart of DOX-induced mice. Our results showed that PPARα gene delivery reduced cardiac dysfunction and mitochondria-dependent apoptosis in DOX-induced mice. Furthermore, we found that PPARα directly regulated the expression of mesenchyme homeobox 1 (MEOX1). Most importantly, the cardioprotective effects of PPARα could be neutralized by knocking down MEOX1. In summary, PPARα plays a vital role in DOX-induced cardiotoxicity and is a promising treatment target.
| S-EPMC7578427 | biostudies-literature
Project description:Doxorubicin-induced cardiotoxicity (DIC) adversely impacts patients' long-term health and quality of life. Its underlying mechanism is complex, involving regulatory cell death mechanisms, such as ferroptosis and autophagy. Moreover, it is a challenge faced by patients undergoing cardiac rehabilitation. Endurance exercise (E-Exe) preconditioning effectively counters DIC injury, potentially through the adenosine monophosphate-activated protein kinase (AMPK) pathway. However, detailed studies on this process's mechanisms are scarce. Here, E-Exe preconditioning and DIC models were established using mice and primary cultured adult mouse cardiomyocytes (PAMCs). Akin to ferrostatin-1 (ferroptosis inhibitor), rapamycin (autophagic inducer), and MitoTEMPO (mitochondrial free-radical scavenger), E-Exe preconditioning effectively alleviated Fe2+ accumulation and oxidative stress and improved energy metabolism and mitochondrial dysfunction in DIC injury, as demonstrated by multifunctional, enzymatic, and morphological indices. However, erastin (ferroptosis inducer), 3-methyladenine (autophagic inhibitor), adenovirus-mediated AMPKα2 downregulation, and AMPKα2 inhibition by compound C significantly diminished these effects, both in vivo and in vitro. The results suggest a non-traditional mechanism where E-Exe preconditioning, under mild mitochondrial reactive oxygen species generation, upregulates and phosphorylates AMPKα2, thereby enhancing mitochondrial complex I activity, activating adaptive autophagy, and improving myocardial tolerance to DIC injury. Overall, this study highlighted the pivotal role of mitochondria in myocardial DIC-induced ferroptosis and shows how E-Exe preconditioning activated AMPKα2 against myocardial DIC injury. This suggests that E-Exe preconditioning could be a viable strategy for patients undergoing cardiac rehabilitation.
| S-EPMC10878110 | biostudies-literature
Project description:ObjectiveDoxorubicin (DOX)-induced cardiotoxicity limits the application of DOX in cancer patients. Currently, there is no effective prevention or treatment for DOX-induced cardiotoxicity. The cellular repressor of E1A-stimulated genes (CREG1) is a cardioprotective factor that plays an important role in the maintenance of cardiomyocytes differentiation and homeostasis. However, the role and mechanism of CREG1 in DOX-induced cardiotoxicity has not yet been elucidated.MethodsIn vivo, C57BL/6J mice, CREG1 transgenic and cardiac-specific CREG1 knockout mice were used to establish a DOX-induced cardiotoxicity model. H&E staining, Masson's trichrome, WGA staining, real-time PCR, and western blotting were performed to examine fibrosis and ferroptosis in the myocardium. In vitro, neonatal mouse cardiomyocytes (NMCMs) were cultured and stimulated with DOX, CREG1-overexpressed adenovirus, and small interfering RNA was used to establish CREG1 overexpression or knockdown cardiomyocytes. Transcriptomics, real-time PCR, western blotting, and immunoprecipitation were used to examine the roles and mechanisms of CREG1 in cardiomyocytes ferroptosis.ResultsThe mRNA and protein levels of CREG1 were reduced in the hearts and NMCMs after DOX treatment. CREG1 overexpression alleviated myocardial damage and inhibited DOX-induced ferroptosis in the myocardium. CREG1 deficiency in the heart aggravated DOX-induced cardiotoxicity and ferroptosis. In vitro, CREG1 overexpression inhibited cardiomyocytes ferroptosis induced by DOX, and CREG1 knockdown aggravated DOX-induced cardiotoxicity. Mechanistically, CREG1 inhibited the mRNA and protein expression of pyruvate dehydrogenase kinase 4 (PDK4) by regulating the F-box and WD repeat domain containing 7 (FBXW7)-forkhead box O1 (FOXO1) pathway. PDK4 deficiency reversed the effects of CREG1 knockdown on cardiomyocytes ferroptosis following DOX treatment.ConclusionCREG1 alleviated DOX-induced cardiotoxicity by inhibiting ferroptosis in cardiomyocytes. Our findings may help clarify the new roles of CREG1 in the development of DOX-induced cardiotoxicity.
| S-EPMC11345695 | biostudies-literature
Project description:BackgroundDoxorubicin (DOX)-induced cardiotoxicity (DIC) is a major impediment to its clinical application. It is indispensable to explore alternative treatment molecules or drugs for mitigating DIC. WGX50, an organic extract derived from Zanthoxylum bungeanum Maxim, has anti-inflammatory and antioxidant biological activity, however, its function and mechanism in DIC remain unclear.MethodsWe established DOX-induced cardiotoxicity models both in vitro and in vivo. Echocardiography and histological analyses were used to determine the severity of cardiac injury in mice. The myocardial damage markers cTnT, CK-MB, ANP, BNP, and ferroptosis associated indicators Fe2+, MDA, and GPX4 were measured using ELISA, RT-qPCR, and western blot assays. The morphology of mitochondria was investigated with a transmission electron microscope. The levels of mitochondrial membrane potential, mitochondrial ROS, and lipid ROS were detected using JC-1, MitoSOX™, and C11-BODIPY 581/591 probes.ResultsOur findings demonstrate that WGX50 protects DOX-induced cardiotoxicity via restraining mitochondrial ROS and ferroptosis. In vivo, WGX50 effectively relieves doxorubicin-induced cardiac dysfunction, cardiac injury, fibrosis, mitochondrial damage, and redox imbalance. In vitro, WGX50 preserves mitochondrial function by reducing the level of mitochondrial membrane potential and increasing mitochondrial ATP production. Furthermore, WGX50 reduces iron accumulation and mitochondrial ROS, increases GPX4 expression, and regulates lipid metabolism to inhibit DOX-induced ferroptosis.ConclusionTaken together, WGX50 protects DOX-induced cardiotoxicity via mitochondrial ROS and the ferroptosis pathway, which provides novel insights for WGX50 as a promising drug candidate for cardioprotection.
| S-EPMC10655295 | biostudies-literature
Project description:Ferroptosis is a regulated necrosis process driven by iron-dependent lipid peroxidation. Although ferroptosis and cellular metabolism interplay with one another, whether mitochondria are involved in ferroptosis is under debate. Here, we demonstrate that mitochondria play a crucial role in cysteine-deprivation-induced ferroptosis but not in that induced by inhibiting glutathione peroxidase-4 (GPX4), the most downstream component of the ferroptosis pathway. Mechanistically, cysteine deprivation leads to mitochondrial membrane potential hyperpolarization and lipid peroxide accumulation. Inhibition of mitochondrial TCA cycle or electron transfer chain (ETC) mitigated mitochondrial membrane potential hyperpolarization, lipid peroxide accumulation, and ferroptosis. Blockage of glutaminolysis had the same inhibitory effect, which was counteracted by supplying downstream TCA cycle intermediates. Importantly, loss of function of fumarate hydratase, a tumor suppressor and TCA cycle component, confers resistance to cysteine-deprivation-induced ferroptosis. Collectively, this work demonstrates the crucial role of mitochondria in cysteine-deprivation-induced ferroptosis and implicates ferroptosis in tumor suppression.
| S-EPMC6338496 | biostudies-literature
Project description:Psoriasis is histologically characterized by keratinocytes (KC) hyperproliferation, inflammation, and increased angiogenesis, but the pathological factor responsible for these symptoms is unknown. Here, a neuroendocrine peptide (prokineticin 2, PK2), is highly expressed in human and mouse psoriatic skins but no significant change in other autoimmune diseases, suggesting that PK2 is a psoriasis-specific factor. Bacterial products significantly up-regulated PK2, implying that infection induces PK2 over-expression. PK2 promoted KC and macrophage to produce interleukin-1 (IL-1), the central player of inflammation and psoriasis, which acts on adjacent fibroblast to induce inflammatory cascades and KC hyperproliferation. IL-1 feeds back on macrophages to induce PK2 production to perpetuate PK2-IL-1 positive feedback loop. PK2 also promoted angiogenesis, another psoriatic symptom. In mouse models, PK2 over-expression aggravated psoriasis while its knock-down inhibited pathological development. The results indicate that PK2 over-production perpetuates psoriatic symptoms by creating PK-2-IL-1 vicious loop. PK2 is a central player in psoriasis and a promising psoriasis-specific target.
| S-EPMC5264273 | biostudies-literature
Project description:Although doxorubicin (DOX) is an efficient chemotherapeutic drug for human tumors, severe cardiotoxicity restricts its clinical use. Cinnamaldehyde (CA), a bioactive component isolated from Cinnamonum cassia, possesses potent anti-oxidative and anti-apoptotic potentials. The major aim of this study was to evaluate the protective role of CA against DOX-induced cardiotoxicity. To this end, cardiomyocyte injury models were developed using DOX-treated H9c2 cells and DOX-treated rats, respectively. Herein, we found that CA treatment increased cardiomyocyte viability and attenuated DOX-induced cardiomyocyte death in vitro. CA further protected rats against DOX-induced cardiotoxicity, as indicated by elevated creatine kinase (CK) and lactate dehydrogenase (LDH) levels, myocardium injury, and myocardial fibrosis. CA alleviated DOX-induced myocardial oxidative stress by regulating reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) levels. Mechanistically, CA markedly accelerated nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2) and increased heme oxygenase-1 (HO-1) expression. Consequently, CA decreased DOX-induced cardiomyocyte ferroptosis, while Erastin (a ferroptosis agonist) treatment destroyed the effect of CA on increasing cardiomyocyte viability. Taken together, the current results demonstrate that CA alleviates DOX-induced cardiotoxicity, providing a promising opportunity to increase the clinical application of DOX.
| S-EPMC10569550 | biostudies-literature