Echinacoside ameliorates doxorubicin‑induced cardiac injury by regulating GPX4 inhibition‑induced ferroptosis
- Authors:
- Published online on: November 23, 2023 https://doi.org/10.3892/etm.2023.12317
- Article Number: 29
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Copyright: © Ma et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Heart failure (HF) is now one of the most common causes of cardiovascular disease, with increasing morbidity and mortality rates (1), and HF occurrence is closely related to the long-term survival of patients with acute coronary syndrome (2). Chronic HF (CHF) is a common complication of several heart diseases, characterized by impaired ventricular filling and ejection (3). Diabetes, hypertension, coronary heart disease, and chronic renal diseases are all risk factors for CHF (4). Doxorubicin (DOX) is an anthracycline initially extracted and identified from Streptomyces pneumonia (5). The highly effective anticancer drug DOX causes progressive cardiac remodeling due to myocardial damage during the early stages of treatment and leads to cardiomyopathy in the later periods (6), involving the excessive generation of reactive oxygen species (ROS), mitochondrial dysfunction, and cardiomyocyte death, frequently resulting in hospitalization (7,8). Additionally, cardiac cell injury, left ventricular dysfunction, and congestive HF associated with a high dose of DOX treatment further worsen a patient's quality of life (9). DOX-induced cardiotoxicity is a side effect when used to treat CHF.
Ferroptosis is a relatively newly discovered type of programmed cell death characterized by iron overload-induced production of large amounts of ROS and lipid peroxide flocking (10). Excessive death of myocardial cells can lead to various cardiovascular diseases and even develop into HF, so developing ideal treatment plans based on pathogenesis is of great significance for cardiopathy (11). Cardiac remodeling is widely accepted as the primary mechanism underlying the progression of HF (12). Cardiac remodeling causes myocardial fibrosis and hypertrophy, resulting in cardiac size, shape, and functional changes, eventually leading to cardiac systolic or diastolic dysfunction (13). Current studies have found that the mechanisms related to ferroptosis, including iron homeostasis imbalance, GSH deficiency, oxidative stress, cardiac stimulation, and mitochondrial dysfunction, play a role in cardiac remodeling (14). Substantial evidence has shown a close relationship between HF pathogenesis and the mechanism of ferroptosis, as the mechanism of HF and ferroptosis has been studied (15). Iron homeostasis is a complex process regulated by multiple iron metabolism proteins; iron homeostasis imbalances can lead to iron overload and ferroptosis. Iron homeostasis plays an important role in maintaining normal heart physiological function, which is susceptible to iron overload, resulting in oxidative stress, and promoting the development of HF (16). Furthermore, the activation center of GPX4 is an important component of cysteine and prevents ferroptosis caused by lipid ROS, implying that GPX4-related ferroptosis may be important in CHF.
Echinacoside (ECH) is a natural bioactive compound isolated from the natural herbs Cistanche and Echinacea. ECH has several biological and pharmacological activities, including anti-apoptotic, neuroprotective, hepatoprotective, immunomodulatory, anti-aging, anti-diabetic, and bone formation-promoting properties (17,18). However, there are no studies assessing the cardioprotective effects of ECH in CHF to the best of our knowledge, and the potential underlying mechanisms remain elusive. Thus, the aim of the present study was to investigate the effects of ECH in GPX4 inhibition-induced ferroptosis of cardiomyocytes in vivo and in vitro.
Materials and methods
Cell culture and treatment
Rat H9c2 cells were obtained from The Cell Bank of Type Culture Collection of The Chinese Academy of Sciences. Cells were cultured in DMEM supplemented with 10% FBS, 2 mM l-glutamine, and 1% penicillin/streptomycin (all from Thermo Fisher Scientific, Inc.) at 37˚C in a humidified incubator supplied with 5% CO2 air. DOX (2 µM, MilliporeSigma, cat. no. 25316-40-9) was used to create the model of using H9c2 cells pretreated for 24 h with or without 5, 10, or 20 µM ECH (purity: ≥99.85%; MedChemExpress, cat. no. HY-N0020). Otherwise, 35 µM erastin was used to induce ferroptosis in H9c2 cells pretreated for 24 h with or without 10 µM ECH.
CCK-8 assay
The CCK-8 assay (Signalway Antibody LLC) was used to detect cell proliferation. Cells were incubated with CCK-8 solution for 1 h after 0 and 24 h in culture. Cell proliferation was measured using a microplate reader, and optical densities at 450 nm were assessed. Each experiment was repeated three times.
Knockdown of Gpx4
Short hairpin-interfering RNAs (shRNA) targeting rat Gpx4 (shGpx4-1: 5'-GGTTTGACATGTACAGCAA-3', site: 377-398; shGpx4-2, 5'-GAAGTAATCAAGAAATCAA-3', site: 332-353; and shGpx4-3 5'-GGATGAAAGTCCAGCCCAA-3', site: 437-458) and scramble shRNA (5'-GGACGAGCTGTACAAGTAA-3') were produced by General Bio Co., Ltd. and assembled into lentiviral plasmids (pLKO.1). Recombinant plasmids were expressed in 293T cells in the presence of psPAX2 and pMD2G using Lipofectamine® 2000 (Thermo Fisher Scientific, Inc.) as per the manufacturer's instructions to produce transducer plasmids. After 48 h, cells were transduced with the pLKO.1-scramble shRNA (shNC) as a negative control.
Measurement of biochemical indices
The Fe2+ concentration in H9c2 cells was determined using an Iron Assay kit (cat. no. ab83366, Abcam), and the LDH (cat. no. A020-1-1), GSH (cat. no. A006-2-1), and MDA levels (cat. no. A003-1-1) in H9c2 cells or serum samples were determined using commercial biochemical kits (Jiancheng Bioengineering Institute). All procedures were performed in accordance with the manufacturer's protocols.
Lipid peroxidation assessment using C11-BODIPY
A total of 10 µM C11-BODIPY (Thermo Fisher Scientific, Inc.) was added to the cell suspension (1x106 cells/ml), and the suspension was incubated in the dark at 37˚C for 30 min. Cells were then washed with PBS, and the fluorescence intensity of the dye C11-BODIPY was measured using an Accuri™ C6 flow cytometer (BD Biosciences, Inc.). Data were analyzed using FlowJo version 7.6.1 (FlowJo LLC).
Reverse transcription-quantitative (RTq)PCR
Total RNA of different samples was extracted using TRIzol® Reagent (Invitrogen; Thermo Fisher Scientific, Inc.). Using a cDNA synthesis kit, RNA was reverse-transcribed into cDNA using a PrimeScript™ kit (Takara Biotechnology Co., Ltd.) according to the manufacturer's protocol. For qPCR, the thermocycling conditions were: 95˚C for 10 min; followed by 40 cycles of 95˚C for 15 sec and 60˚C for 45 sec, and Gapdh was used as the loading control. The relative gene expression was calculated using the 2-ΔΔCq method (19). Data are presented as the mean of three replicates. Table I contains the sequences of all the primers.
Western blot analysis
RIPA lysis buffer (JRDUN) was used to lyse the samples, and the protein yield was determined using an enhanced BCA protein assay kit (Thermo Fisher Scientific, Inc.). Total proteins were separated by 10% SDS-PAGE and transferred to a nitrocellulose membrane overnight before being blocked with 5% nonfat dry milk overnight at 4˚C. Subsequently, membranes were incubated with one of the primary antibodies overnight at 4˚C, followed by secondary antibody anti-mouse IgG (cat. no. A0208; Beyotime Institute of Biotechnology; 1:1,000) for 1 h at 37˚C. Signals were visualized and densitometry analysis was performed using an enhanced chemiluminescence system (Bio-Rad Laboratories, Inc.). The primary antibodies were used: GPX4 (cat. no. DF6701; Affinity Biosciences Ltd.; 1:1,000), PTGS2 (cat. no. AF7003; Affinity Biosciences Ltd.; 1:1,000), and GAPDH (cat. no. #5174s; Cell Signaling Technology, Inc.; 1:30,000).
Rat model of CHF and treatments
Male Sprague-Dawley rats weighing 180-220 g were purchased from HFK Bioscience Co. Ltd. All experimental procedures were performed in accordance with the Guidelines for the Institutional Animal Care and Use Committee of Shanghai Rat & Mouse Biotech Co., Ltd. (Approval no. 202109) (18). All procedures followed internationally recognized ethical standards. The rats were divided into the following four groups (n=6 per group): normal group, DOX group (rat model of CHF), DOX + E50 group (DOX + ECH 50 mg/kg), and DOX + E100 group (DOX + ECH 100 mg/kg). A CHF rat model was induced by DOX (intraperitoneal injection of 2.5 mg/kg, twice a week) as previously described (7). Furthermore, the rats were given ECH (50 or 100 mg/kg) by gavage for 2 weeks. To monitor cardiac function, an echocardiogram was performed, and hemodynamic variables were assessed (20). After treatment completion, the animals were anesthetized with 2% sodium pentobarbital (50 mg/kg) (B005, Jiancheng Bioengineering Institute) and sacrificed by cervical dislocation, and their hearts were removed. Myocardial tissues were fixed in 4% paraformaldehyde overnight at 4˚C, dehydrated in ascending ethanol gradient and embedded in paraffin for 2 h at room temperature and made into paraffin sections (5 µm). Subsequently, the sections were placed in an oven and heated at 60˚C for 1 h, immersed in xylene solution at room temperature for 10 min, and then immersed in descending ethanol gradient at room temperature for 5 min, followed by staining with hematoxylin and eosin at room temperature for 5 and 3 min, respectively, using an H&E staining kit (cat. no. C0105S; Beyotime Institute of Biotechnology). After dehydrating in 100% alcohol at room temperature for 5 min and mounting, tissues were observed under a microscope. Blood samples were taken from the abdominal aorta to detect brain natriuretic peptide (BNP) using a BNP ELISA Kit (cat. no. E-EL-R0126c; Elabscience Biotechnology, Inc.).
Statistical analysis
GraphPad Prism version 8.4.2 (GraphPad Software, Inc.) was used for statistical analysis. Data are presented as the mean ± standard deviation. Comparisons between two groups were performed using a Student's t-test, whereas an ANOVA followed by a Tukey's post hoc test was used to compare multiple groups. P<0.05 was considered to indicate a statistically significant difference.
Results
ECH ameliorates DOX-mediated increases in LDH and MDA levels and decreases in GSH levels in rat H9c2 cells
To determine the optimal concentration of ECH for regulating DOX-induced rat H9c2 cell cytotoxicity, H9c2 cells were cultured with ECH at various concentrations (5-20 µM) for 24 h, and the cell proliferation activity was detected using a CCK-8 assay kit (Fig. 1A). When 20 µM ECH was used, cell proliferation activity decreased significantly and in a dose-dependent manner. The MDA, GSH, and LDH levels were also measured. The MDA and LDH levels were elevated by DOX, whereas ECH significantly reduced this trend (Fig. 1B and C). Furthermore, when compared to the control group, the GSH levels in the DOX group were significantly lower, and an increase in this level was observed after ECH treatment (Fig. 1D).
ECH ameliorates DOX-induced ferroptosis in rat H9c2 cells
The mechanisms related to ferroptosis, such as iron homeostasis imbalance, GSH deficiency, oxidative stress, cardiac stimulation, and mitochondrial dysfunction, play a role in cardiac remodeling (14). Moreover, our previous study found that DOX caused cardiac injury by activating cardiomyocyte ferroptosis (7). Therefore, the effects of ECH on DOX-induced Fe2+ and lipid ROS in H9c2 cells were assessed. Interestingly, it was found that DOX exposure increased the Fe2+ levels in H9c2 cells by threefold when compared to the control group. However, ECH significantly reduced this elevation in a dose-dependent manner (from 5-20 µM; Fig. 2A). When H9c2 cells were treated with DOX, they produced significantly more lipid ROS as compared to the control group. Meanwhile, lipid ROS levels in the ECH groups were significantly reduced in a dose-dependent manner (Fig. 2B and C). GPX4 is currently recognized as a central inhibitor of ferroptosis, and its activity depends on glutathione produced by cystine-glutamate antitransporter solute carrier family seven member 11 (SLC7A11) activation, which is considered an anti-ferroptosis molecule (21). Additionally, transferrin receptor protein 1 (TFRC) is the key receptor mediating the cellular uptake of iron, and solute carrier family 11 member 2 (SLC11A2) is involved in the release of irons from acidified endosomes into the cytoplasm (22). Prostaglandin-endoperoxide synthase 2 (PTGS2) plays dual functions as both a cyclooxygenase and peroxidase, and is known to be induced by various ferroptosis inducers (22). Thus, the mRNA levels of hub ferroptosis-related genes Tfrc, Slc11a2, Slc7a11, Gpx4, and Ptgs2 in cells were assessed. DOX exposure significantly increased the mRNA expression levels of Tfrc, Slc11a2, Slc7a11, and Ptgs2, while decreasing the mRNA expression levels of Gpx4. However, ECH significantly increased the mRNA expression levels of Gpx4 and decreased the Ptgs2 mRNA expression levels in DOX-treated rat H9c2 cells in a dose-dependent manner (Fig. 2D). These two proteins were therefore further examined by western blotting. DOX decreased GPX4 protein expression while increasing PTGS2 protein expression, and this was inhibited by ECH (Fig. 2E).
ECH inhibits erastin-induced ferroptosis in rat H9c2 cells
To further examine the role of ECH in ferroptosis in rat H9c2 cells, the ferroptosis inducer erastin was used. As illustrated in Fig. 3A, cell proliferation decreased significantly in erastin-treated cells, whereas ECH significantly increased cell proliferation after 24 h. Moreover, erastin significantly increased the lipid ROS levels, and ECH reversed this (Fig. 3B and C). When compared to the control group, erastin exposure reduced GPX4 expression while increasing PTGS2 expression, but ECH could reverse these effects (Fig. 3D).
Knockdown of Gpx4 inhibits the protective effects of ECH on DOX-induced accumulation of lipid ROS in rat H9c2 cells
shRNA targeting of Gpx4 was used to investigate the effects of GPX4 on the protective effects of ECH on DOX-induced ferroptosis in rat H9c2 cells. Western blot analysis revealed that using specific Gpx4 shRNAs (Fig. 4A and B) significantly reduced Gpx4 expression when compared to the shNC group. Furthermore, ECH significantly reduced the DOX-induced increases in lipid ROS levels, whereas shGpx4 reversed this effect (Fig. 4C and D). Additionally, Western blotting data showed that DOX inhibited GPX4 expression while increasing PTGS2 expression; however, this trend was reversed by the knockdown of Gpx4 (Fig. 4E). These findings showed that knockdown of Gpx4 inhibited the protective effects of ECH on DOX-induced accumulation of lipid ROS in rat H9c2 cells.
ECH ameliorates DOX-induced CHF in rats
DOX was used to establish a CHF rat model to assess the effects of ECH on CHF in vivo. DOX reduced the left ventricular ejection fraction, fractional shortening, end-systolic pressure, and heart rate while increasing left ventricular end-diastolic pressure (Table II). Conversely, ECH may improve DOX-induced cardiac function. Tissue sections from the control group exhibited a normal morphology, whereas those from DOX-treated rats exhibited myocardial disorganization, increased intracellular spaces, and cytoplasmic vacuolization (Fig. 5A). Moreover, eosinophilic cells with pyknotic nuclei and loss of myofibrils were observed among cardiomyocytes in the DOX-treated rats (Fig. 5A). However, ECH administration resulted in a considerable improvement in the histopathology as compared to that observed in the DOX group; the histological appearance of high-dose ECH group was similar to that of the control group (Fig. 5A). Given that BNP is an important indicator of ventricular function, the BNP levels in the CHF rat model were measured by ELISA. The findings revealed that, when compared to the control group, DOX exposure significantly increased the BNP levels, whereas ECH exposure decreased the BNP levels in a dose-dependent manner (Fig. 5B). LDH is an enzyme found in myocardial cell damage. DOX significantly increased the LDH levels compared with the control group, whereas ECH administration reversed this effect (Fig. 5C). Of note, the effect of ECH on the protein expression levels of GPX4 and PTGS2 matched the in vitro findings, which showed that ECH administration reversed the effects in the CHF rat model (Fig. 5D).
Discussion
HF is a complicated clinical syndrome characterized by cardiac systolic and diastolic dysfunction (23). Despite numerous clinical and experimental studies on the treatment of CHF, a satisfactory treatment regimen to prevent HF progression is lacking (24). Hence, it is critical to find a safe and effective therapeutic to treat HF. ECH has been studied for its potential to protect against HF (25). The effect and molecular mechanism of HF, however, are unknown.
In the present study, ECH protected DOX-treated H9c2 cells from oxidative stress and ferroptosis. Furthermore, ECH alleviated DOX-induced cardiac injury by regulating GPX4 inhibition-induced ferroptosis. A growing body of evidence suggests that oxidative stress is a direct or indirect pathophysiological pathway in the HF process (26). Excess ROS production causes cellular protein, lipid, and DNA damage, and the physiological antioxidant defense system cannot eliminate it, resulting in cell necrosis and apoptosis (27). MDA is formed as the result of lipid oxidation by oxygen-free radicals, causing cytotoxicity and worsening cell membrane damage, and is commonly used to reflect the degree of oxidative stress (28,29). However, an excess of ROS leads to an excess of lipid peroxide conversion in HF development. Meanwhile, MDA production increases, activating a feedforward loop mechanism, and oxidative stress increases, resulting in further deterioration of myocardial systolic and diastolic functions (30). DOX was found to increase the production of inflammatory cytokines during cardiotoxicity and oxidative stress (31,32). When patients develop HF, the plasma BNP levels are markedly increased, and the degree of increase is related to the degree of ventricular dilatation, which is widely used as an HF biomarker, and is involved in ventricular dysfunction; that is, the content of BNP is closely associated with HF severity (33,34). In the present study, the effects of ECH on DOX-induced BNP in plasma for the alleviation of HF symptoms were investigated. The results showed that ECH effectively alleviated cardiac injury in vivo and in vitro.
As more evidence emerged that myocardial cell ferroptosis is associated with myocardial ischemia-reperfusion injury, which plays a role in HF development, it was shown that ferroptosis inhibition could improve myocardial injury and HF (35-38). Ferroptosis is caused by an imbalance in the production and clearance of intracellular lipid peroxides (39). Ferroptosis involves lipid, GSH, and iron metabolisms, and mitochondrial dysfunction. When cells experience iron overload, the ROS levels increase, resulting in intracellular lipid peroxide accumulation, and iron overload in cardiomyocytes results in oxidative stress and mitochondrial damage, eventually leading to systolic and diastolic dysfunction and myocardial fibrosis (40,41). Iron overload damages the heart by causing oxidative stress, promoting HF development (42). According to research, inhibiting GSH synthesis increases cardiac lipid peroxidation, which inhibits myocardial contractility (43). One of the ferroptosis-related proteins is GPX4, and selenium deficiency is a risk factor for HF development. By lowering the GPX4 activity, selenium deficiency promotes CHF progression. PTGS2 participated in the prostaglandin biosynthesis process, which catalyzes lipid oxidation and is involved in ferroptosis (44). Furthermore, it was discovered that ECH administration decreased PTGS2 expression while increasing GPX4 expression in DOX-treated rats and H9c2 cells. As a regulator of ferroptosis, GPX4 induces ferroptosis by inhibiting its substrate glutathione or glutathione components (45). When cardiomyocytes produce a large amount of ROS, the cell's antioxidant activity is reduced, and lipid ROS are produced, inhibiting GSH absorption, and the GSH levels are associated with HF severity (46). GSH deficiency causes cysteine deficiency, lowering the GPX4 activity and resulting in ferroptosis. Furthermore, Gpx4 knockdown inhibited the protective effects of ECH on DOX-induced accumulation of lipid ROS in rat H9c2 cells, indicating that ECH could protect DOX-induced cardiac injury by affecting ferroptosis hub proteins. These important findings provide a foundation for the clinical treatment of CHF. Owing to the limited literature reports on the involvement of ferroptosis in CHF, the present study may be considered for developing a potential therapy for the disease based on targeting of ferroptosis.
In conclusion, ECH ameliorated DOX-induced cardiac injury by regulating GPX4 inhibition-induced ferroptosis. Thus, ECH may serve as a promising and important therapy for the treatment of CHF injury.
Acknowledgements
Not applicable.
Funding
Funding: The present study was financially supported by the Shanghai Pudong Commission of Health and Family Planning (grant no. PW2020D-10), Shanghai Municipal Commission of Health and Family Planning (grant no. 202040188), Medical Disciplinary Development Project of Pudong New Area Health System (grant no. PWYgy2021-10) and Multiplication plan for traditional Chinese medicine specialty brand building (grant no. PDZY-2021-0310).
Availability of data and material
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
YM, SZ, and JZ conceived and designed the study. YM wrote, reviewed, and revised the manuscript. XY, NJ, CL and JZ acquired, analyzed, and interpreted the data, and performed the statistical analysis. YM, SZ, and JZ confirm the authenticity of all the raw data. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
All experimental procedures were performed in accordance with the Guidelines for the Institutional Animal Care and Use Committee of Shanghai Rat & Mouse Biotech Co., Ltd. (approval no. 202109).
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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