Myocardial infarction (MI) triggers dynamic tissue remodeling in which fibroblast activation critically determines scar formation and long-term cardiac function. Although iron dysregulation has been implicated in acute myocardial injury, its role in non-cardiomyocyte remodeling remains incompletely understood. Here, we integrated cross-species transcriptomics, spatial transcriptomics, single-cell RNA sequencing, and functional studies to investigate iron metabolic remodeling after MI. We found that ferritin heavy chain (Fth1) was robustly induced in the infarct region during the proliferative phase after MI and was predominantly localized to macrophages and fibroblasts. Single-cell trajectory analysis revealed that high Fth1 expression characterized early or inflammatory fibroblast states, whereas progressive Fth1 downregulation accompanied differentiation into extracellular matrix-producing myofibroblasts. Functionally, ferritin depletion promoted fibroblast activation in both neonatal rat and adult mouse cardiac fibroblasts, accompanied by expansion of the intracellular labile iron pool (LIP) and enhanced pro-fibrotic gene expression. Mechanistically, intracellular iron chelation suppressed fibroblast activation and was associated with alterations in FoxO1-related transcriptional programs. Notably, temporally targeted treatment with the cell-permeable iron chelator 2,2'-bipyridyl (BPD) during the proliferative phase (days 3-14), but not the acute inflammatory phase (days 0-3), effectively attenuated pathological fibrosis and improved cardiac function after MI. Transcriptomic profiling further showed that iron chelation modulated both fibroblast activation-associated and inflammatory gene programs within the infarcted myocardium. Collectively, these findings identify ferritin-regulated iron homeostasis as a key determinant of fibroblast plasticity and highlight phase-specific intracellular iron modulation as a potential therapeutic strategy for limiting adverse cardiac remodeling after MI.

INTRODUCTION:Polycystic ovarian syndrome (PCOS) is a common reproductive disorder that affects a considerable number of women worldwide. Nevertheless, the causal relationship between metabolites and PCOS remains undetermined. METHODS:We utilized a comprehensive two-sample Mendelian randomization (MR) analysis, a genetic epidemiological approach that uses genetic variants as instrumental variables to assess causal relationships between exposures and outcomes, to examine the causal link between 1352 metabolites and PCOS. We employed complementary MR methods, such as the inverse-variance weighted (IVW) method, and conducted sensitivity analyses to evaluate the reliability of the outcomes. Reverse MR analysis was performed to evaluate the possibility of reverse causation. RESULTS:Five metabolites were identified to be significantly associated with PCOS risk: Methionine sulfoxide levels (IVW: OR [95%]: 1.549[1.274 to 1.883], p = 1.154E-5), Theophylline levels (IVW: OR [95%]: 0.725[0.589 to 0.890], p = 0.002), 4-hydroxycoumarin levels (IVW: OR [95%]: 0.786[0.658 to 0.940], p = 0.008), Tyramine O-sulfate levels (IVW: OR [95%]: 0.699[0.568 to 0.862], p = 0.0008), and Sulfate of piperine metabolite C16H19NO3 (3) levels (IVW: OR [95%]: 1.296[1.064 to 1.579], p = 0.009). We found PCOS was significantly associated with decreased Tyramine O-sulfate levels using the IVW method (OR [95%]: 0.953[0.917 to 0.991], p = 0.015) in the reverse MR analysis. The results of the sensitivity analyses were consistent with the main findings. DISCUSSION:This study establishes causal relationships between specific metabolites and PCOS, highlighting the significant roles of oxidative stress (methionine sulfoxide), dietary components (theophylline, piperine metabolite), and gut microbiome-derived metabolites. These findings provide novel insights into PCOS pathogenesis and identify potential targets for prevention and treatment. However, the study's limitation to European populations necessitates further validation in diverse ethnic groups. CONCLUSION:Our MR analysis provides strong evidence supporting a causal association between metabolites and the susceptibility of PCOS.

Sarcopenia, a condition characterized by the gradual decline of muscle mass, strength, and function, is a key indicator of malnutrition in cancer patients and has been linked to poor prognoses in oncology. Sarcopenia is commonly assessed by measuring the skeletal muscle index (SMI) of the third lumbar spine (L3) using computed tomography (CT). This meta-analysis aimed to explore the relationship between low SMI and clinicopathological features, as well as prognosis, in individuals with endometrial cancer (EC). Data from various databases including PubMed, Embase, Cochrane, Medline, and Web of Science were searched up until October 20th, 2024. Studies that investigated the association of low SMI and EC survival or clinicopathological characteristics were included. Pooled effect sizes were reported as hazards ratio (HR), odds ratios (ORs) or weighted mean difference (WMD). The quality and risk of bias in the studies were evaluated using the Newcastle-Ottawa Scale (NOS) and the Quality In Prognosis Studies (QUIPS), and the study was registered on PROSPERO (CRD42024509949) before commencing the search. A total of 218 studies were identified across all five databases, with 11 studies meeting the criteria for qualitative and quantitative analysis, involving 1588 patients. The findings of our meta-analysis demonstrated a significant link between low SMI and progression-free survival [P = 0.002; HR: 1.62, 95

The widespread use of antifungal triazoles has increasingly been associated with cardiovascular adverse events (AEs), particularly torsade de pointes (TdP) and QT prolongation. Understanding the characteristics of TdP/QT prolongation associated with antifungal triazoles is crucial for their safe and effective administration. In the FAERS database from 2004 to 2024, a total of 18,940 patients with antifungal triazoles were extracted for disproportionality analyses to reflect the degree of association between the TdP/QT prolongation and different antifungal triazoles, and the logistic regression analysis was used to identify potential influencing factors. Additionally, the study examines concomitant medication use in patients who experienced TdP/QT prolongation. Among the overall AEs cases of triazoles, the incidence rate of TdP/QT prolongation was around 2

Endometriosis is a prevalent reproductive disorder that affects a significant number of women globally. Cathepsins, which are lysosomal cysteine proteases, contribute to several physiological and pathological processes, including the attachment and invasion of endometrial tissue. Nevertheless, the causal relationship between cathepsins and endometriosis remains undetermined. The aim of this study was to explore the potential relationship between cathepsins and endometriosis using genetic polymorphisms. We employed a 2-sample Mendelian randomization (MR) analysis (including inverse-variance weighted [IVW] method and reverse MR analysis) to investigate the causal association between 9 cathepsins and endometriosis. The IVW method provides efficient and robust causal estimates when genetic instruments are valid, making it the standard approach in MR analysis. And the reverse MR analysis ensures the robustness and directionality of causal inference. The univariable MR analysis results indicate that Cathepsin H increases the risk of overall endometriosis (IVW: OR [95%] = 1.037 [1.007 to 1.067], P = .013), endometriosis of ovary (IVW: OR [95%] = 1.022 [1.001 to 1.042], P = .046), endometriosis of pelvic peritoneum OR [95%] = 1.046 [1.002 to 1.089], P = .047), and deep endometriosis (IVW: OR [95%] = 1.050 [1.002 to 1.099], P = .048). The multivariable MR analysis retained stable after adjusting for other types of cathepsins. And reverse MR analyses suggest that overall endometriosis may lead to increased Cathepsin H levels (IVW: OR [95%] = 1.017 [1.003, 1.073], P = .041). The results of the sensitivity analyses were consistent with the main findings. Our MR analysis yields robust evidence supporting a causal relationship between Cathepsin H and the susceptibility to endometriosis, potentially inspiring directions in endometriosis diagnosis and treatment.

Although phosphorus is one of the most important essential elements for plant growth and development, the epigenetic regulation of inorganic phosphate (Pi) signaling is poorly understood. In this study, we investigated the biological function and mode of action of the high-mobility-group box 1 protein OsHMGB1 in rice (Oryza sativa), using molecular and genetic approaches. We determined that OsHMGB1 expression is induced by Pi starvation and encodes a nucleus-localized protein. Phenotypic analysis of Oshmgb1 mutant and OsHMGB1 overexpression transgenic plants showed that OsHMGB1 positively regulates Pi homeostasis and plant growth. Transcriptome deep sequencing and chromatin immunoprecipitation followed by sequencing indicated that OsHMGB1 regulates the expression of a series of phosphate starvation-responsive (PSR) genes by binding to their promoters. Furthermore, an assay for transposase-accessible chromatin followed by sequencing revealed that OsHMGB1 is involved in maintaining chromatin accessibility. Indeed, OsHMGB1 occupancy positively correlated with genome-wide chromatin accessibility and gene expression levels. Our results demonstrate that OsHMGB1 is a transcriptional facilitator that regulates the expression of a set of PSR genes to maintain Pi homeostasis in rice by increasing the chromatin accessibility, revealing a key epigenetic mechanism that fine-tune plant acclimation responses to Pi-limited environments.

BackgroundPolycystic ovarian syndrome (PCOS) is a common reproductive disorder that affects a considerable number of women worldwide. It is accompanied by irregular menstruation, hyperandrogenism, metabolic abnormalities, reproductive disorders and other clinical symptoms, which seriously endangers women’s physical and mental health. The etiology and pathogenesis of PCOS are not completely clear, but it is hypothesized that immune system may play a key role in it. However, previous studies investigating the connection between immune cells and PCOS have produced conflicting results.MethodsMendelian randomization (MR) is a powerful study design that uses genetic variants as instrumental variables to enable examination of the causal effect of an exposure on an outcome in observational data. In this study, we utilized a comprehensive two-sample MR analysis to examine the causal link between 731 immune cells and PCOS. We employed complementary MR methods, such as the inverse-variance weighted (IVW) method, and conducted sensitivity analyses to evaluate the reliability of the outcomes.ResultsFour immunophenotypes were identified to be significantly associated with PCOS risk: Memory B cell AC (IVW: OR [95%]: 1.123[1.040 to 1.213], p = 0.003), CD39+ CD4+ %CD4+ (IVW: OR [95%]: 0.869[0.784 to 0.963], p = 0.008), CD20 on CD20- CD38-(IVW: OR [95%]:1.297[1.088 to 1.546], p = 0.004), and HLA DR on CD14- CD16+ monocyte (IVW: OR [95%]:1.225[1.074 to 1.397], p = 0.003). The results of the sensitivity analyses were consistent with the main findings.ConclusionsOur MR analysis provides strong evidence supporting a causal association between immune cells and the susceptibility of PCOS. This discovery can assist in clinical decision-making regarding disease prognosis and treatment options, and also provides a new direction for drug development.

We explored the added value of a radiomic strategy based on quantitative transverse relaxation (T2) mapping and conventional magnetic resonance imaging (MRI) to evaluate the histologic grade of bladder cancer (BCa) preoperatively. Patients who were suspected of BCa underwent pelvic MRI (including T2 mapping and diffusion-weighted imaging (DWI) before any treatment. All patients with histological-proved urothelial BCa were included. We constructed different prediction models using the mean signal values and radiomic features from both T2 mapping and apparent diffusion coefficient (ADC) maps. The diagnostic performance of each model or parameter was assessed using receiver operating characteristic curves. In total, 92 patients were finally included (training cohort, n = 64; testing cohort, n = 28); among these, 71 had high-grade BCa. In the testing cohort, the T2-mapping radiomic model achieved the highest prediction performance (area under the curve (AUC), 0.87; 95% confidence interval (CI), 0.73–1.0) compared with the ADC radiomic model (AUC, 0.77; 95%CI, 0.56–0.97), and the joint radiomic model of 0.78 (95%CI, 0.61–0.96). Our results demonstrated that radiomic mapping could provide more information than direct evaluation of T2 and ADC values in differentiating histological grades of BCa. Additionally, among the radiomic models, the T2-mapping radiomic model outperformed the ADC and joint radiomic models.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are critical for cancer initiation and progression. MicroRNAs (miRNAs) could notably influence the phenotype of TAMs through various targets and signal pathways during cancer progression due to their post-transcriptional regulation. In this review, we discuss mainly the regulatory function of miRNAs on macrophage differentiation, functional polarization, and cellular crosstalk. Firstly, during the generation process, miRNAs take part in the differentiation from myeloid cells to mature macrophages, and this maturation process directly influences their recruitment into the TME, attracted by tumor cells. Secondly, macrophages in the TME can be either tumor-promoting or tumor-suppressing, depending on their functional polarization. Large numbers of miRNAs can influence the polarization of macrophages, which is crucial for tumor progression, including tumor cell invasion, intravasation, extravasation, and premetastatic site formation. Thirdly, crosstalk between tumor cells and macrophages is essential for TME formation and tumor progression, and miRNAs can be the mediator of communication in different forms, especially when encapsulated in microvesicles or exosomes. We also assess the potential value of certain macrophage-related miRNAs (MRMs) as diagnostic and prognostic markers, and discuss the possible development of MRM-based therapies.

BACKGROUND:Ceruloplasmin (Cp) is a major copper-binding protein produced in the liver and delivers copper to extrahepatic organs. Patients with myocardial infarction are often featured by an elevation of serum copper concentrations due to copper efflux from ischemic hearts. The present study was undertaken to test the hypothesis that serum copper elevation leads to up-regulation of hepatic Cp in myocardial infarction.METHODS:Adult male Sprague-Dawley rats were subjected to left anterior descending (LAD) coronary artery ligation to induce myocardial infarction. Serum copper and Cp levels, as well as changes in hepatic Cp and copper-transporting P-type ATPase (Atp7b), were determined from blood and liver samples collected on day 1, 4, or 7 after the operation.RESULTS:Serum copper concentrations were significantly increased on day 4 after LAD ligation, accompanied by an increase in serum Cp levels and activities. Concomitantly, the protein levels of Cp and copper exporter, Atp7b, were also significantly increased in the liver. Furthermore, inhibiting the increase of serum copper by a copper chelator, triethylenetetramine (TETA), effectively abolished the elevated Cp activity after LAD ligation.CONCLUSION:These results indicate that serum Cp elevation in response to myocardial ischemia most likely resulted from the increased hepatic Cp production, which in turn was more responsive to serum copper elevation than inflammatory response following myocardial ischemia.

Immunotherapy for renal cell cancer (RCC) has witnessed several developments for more than two decades. Checkpoint inhibitors, including anti-CTLA-4 and anti-PD-1/PD-L1 blockers, have changed the treatment landscape for patients with advanced RCC in the past 3 years. Despite these advances, more than 55% RCC patients become resistant to different immunotherapies without other treatment combination. Among various attempts at overcoming resistance to immunotherapy, stereotactic body radiotherapy (SBRT) has been found to potentiate the activity of immunotherapy agents through several potential mechanisms, including normalization of microvessels to alleviate tumor hypoxia, improvement in efficient delivery of drugs, abundant neoantigen exposure, and recruitment of antitumor immune cells to alter the immunosuppressive tumor microenvironment. Preclinical studies and clinical case reports have predicted that the combination of SBRT, an immunotherapy, may lead to remarkable results. This review aims to provide the biological basis for the feasibility of combining SBRT to overcome immunotherapy resistance and to review the currently available clinical evidence of this combination therapy in patients with advanced RCC.

Dietary copper supplementation reverses pressure overload-induced cardiac hypertrophy by copper replenishment in the heart. A copper-selective chelator, trientine (triethylenetetramine [TETA]), reverses left ventricular hypertrophy associated with diabetes also by copper replenishment in the heart. The present study was undertaken to address the critical issue how TETA delivers copper to the heart. Adult male Sprague-Dawley rats were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Eight weeks after the TAC surgery, cardiac hypertrophy was developed and copper content in the heart was reduced. TETA was then administrated by gavage in two different dosages (21.9 or 87.6 mg/kg day) for six weeks. The results showed that in the lower dosage, TETA replenished copper contents in the heart, along with a decrease in the copper concentration in the blood and kidney, and an increase in the urine. In the higher dosage, TETA did not replenish copper contents in the heart, but markedly increased copper concentrations in the urine and decreased those in the blood and kidney. Neither lower nor higher TETA dosage altered copper concentrations in other organs. Corresponding to myocardial copper replenishment, the lower dose TETA suppresses cardiac hypertrophy, as judged by a reduction in the left ventricle wall thickness and a decrease in the heart size, and diminished cardiac fibrosis, as reflected by a decrease in collagen I content. TETA in the higher dose not only did not suppress cardiac hypertrophy, but also caused cardiac hypertrophy in sham-operated rats. TETA-mediated myocardial copper restoration is independent of copper transporter-1 or -2 but related to an energy-dependent transportation. This study demonstrates that low-dose TETA functions as a copper chaperone, selectively delivering copper to the copper-deprived heart through an active transportation; in higher doses, TETA simply retains its chelator function, removing copper from the body by urinary excretion. Impact statement Our study reveals that TETA, traditionally regarded as a copper chelator, in lower doses delivers copper selectively to the heart through a mechanism independent of copper transporter-1 or -2. Copper supplementation by a lower dose of TETA suppresses pressure overload-induced cardiac hypertrophy. Since ischemic heart disease and hypertrophic cardiomyopathy are accompanied by myocardial copper loss, this approach of using a lower dose of TETA to supplement copper to the heart would help treat the disease condition of patients with such cardiac events.

Trientine (TETA), a copper (Cu) chelator, is capable of replenishing Cu in the heart, and Cu repletion reduces cardiac fibrosis in a rodent model of cardiac hypertrophy. This study was undertaken to explore possible mechanisms by which Cu repletion diminishes cardiac fibrosis. Adult male Sprague-Dawley rats were subjected to ascending aortic constriction to induce cardiac hypertrophy. Four months after the operation, cardiac hypertrophy along with fibrosis was fully developed. TETA treatment was then followed at a dose of 21.9 mg kg-1, twice a day, administered orally for six weeks. At the end of the treatment, the hearts were harvested and all of the tissue samples were subjected to qRT-PCR, western blot, Sirius red staining, hydroxyproline assay, and immunostaining analyses. TETA treatment significantly increased the content of Cu in the hypertrophied myocardium, decreased type III collagen deposition and reduced cardiac fibrosis. On the other hand, this treatment did not alter the increase in fibroblasts induced by pressure overload, but significantly increased matrix metalloproteinase-2 (MMP-2), which is the enzyme mainly responsible for degradation of collagens in the heart. In addition, the mRNA and protein levels of tissue inhibitors of matrix metalloproteinase-1 and -2 (TIMP-1 and TIMP-2) were both remarkably increased in the hypertrophic myocardium, and normalized after TETA treatment. The data thus demonstrated that the reduction in cardiac fibrosis by TETA-induced Cu repletion is associated at least in part with an enhanced MMP-2 activity, leading to collagen degradation.

Myocardial fibrogenesis is initiated once the coordination between oxygen supply and demand is disrupted in pressure overload-induced cardiac hypertrophy. Clinical observations showed that myocardial fibrosis did not evenly occur in the hypertrophic myocardium. The present study was undertaken to specifically address differential vulnerabilities to fibrogenesis of different regions in the myocardium subjected to pressure overload-induced hypertrophy. SD rats were divided into two groups, sham-operated control and ascending artery constriction-induced cardiac hypotrophy. Thirty-four weeks after surgery, rats were sacrificed and hearts were harvested. Myocardial tissues were processed and sequentially sectioned for detection of collagen deposition, myocyte hypertrophy and vascular density analysis. Redundant collagen stained with Sirius red and anti-collagen I antibody was found in the extracellular matrix, but high volume of collagen fraction was largely localized more in posterior and lateral walls than in anterior wall and interventricular septum, which is in accordance with the accumulation of fibroblasts. In association with the differential regional collagen accumulation, the cardiomyocytes were more hypertrophic in the posterior and lateral wall than the other left ventricle. However, the capillary density in the lateral and posterior walls was significantly decreased. The results indicated that the posterior and lateral walls were more vulnerable to fibrogenesis post-pressure overload-induced cardiac hypertrophy, which was associated with the depressed angiogenesis in these two regions.

Sustained pressure overload leads to cardiac hypertrophy and copper efflux from the heart. Dietary copper supplementation replenishes copper in the heart and reverses cardiac hypertrophy. On the contrary, a copper selective chelator, trientine (TETA), reverses left ventricular hypertrophy associated with diabetes. The present study was undertaken to test the hypothesis that TETA functions as a copper chaperone delivering copper to the heart leading to regression of cardiac hypertrophy. Adult male Sprague‐Dawley rats were subjected to transverse aortic constriction (TAC) to induce cardiac hypertrophy. Eight weeks after the surgery cardiac hypertrophy was developed and myocardial copper was reduced. TETA was then administrated by gavage at two different doses (21.9 mg/kg·day and 87.6 mg/kg·day) for six weeks. The results showed that at lower dose, TETA replenished copper contents in the heart, accompanied by a decrease in blood plasma and an increase in urine of copper concentrations. At higher dose, TETA did not replenish copper contents in the heart, but markedly increased copper concentrations in the urine, along with a decrease in serum copper concentrations. Corresponding to myocardial copper repletion, lower dose TETA reversed cardiac hypertrophy, as judged by a reduction in the left ventricle wall thickness (LVAWd and LVPWd) and a decrease in the heart size (heart weight/tibia length), and diminished cardiac fibrosis, as reflected by a decrease in collagen I content. TETA at higher dose not only did not regressed cardiac hypertrophy, but caused cardiac hypertrophy in sham‐operated rats. This study demonstrates that TETA, at lower dose, functioned as a copper chaperone delivering copper to the heart of copper deprivation and, at higher dose, simply remained its chelator function removing copper from the body by urinary excretion.Support or Funding InformationSupported by National Science Foundation of China (81230004 and 81300109).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The selection of anesthetics for patients with myocardial infarction is critically challenging. Sevoflurane is a volatile anesthetic gradually used in recent years. The intraoperative hemodynamic stability of sevoflurane was supported by several studies with some suggestions for its use for patients with cardiac events. The present study was undertaken to investigate the effect of sevoflurane on mice with myocardial infarction to evaluate the safety issue of this agent for possible application in patients with myocardial infarction. Mice of 7–12 weeks old were subjected to left anterior descending artery ligation to introduce acute myocardial infarction. The effect of sevoflurane on the hemodynamics was examined in comparison with that of currently available agent etomidate at low and moderate doses. The results showed that sevoflurane caused unstable hemodynamic changes in mice with myocardial infarction at both low and moderate inhaled concentrations relative to low and moderate doses of etomidate. In addition, the relative safety margin estimated from therapeutic index was decreased by 50 % when sevoflurane was used for mice with myocardial infarction relative to control mice, but only decreased by 20 % for etomidate. These analyses indicate that in comparison with currently available agent etomidate, sevoflurane should not be applied to patients with myocardial infarction or other cardiac events.

PURPOSE:Miniaturized percutaneous nephrolithotomy (MPCNL), including minipercutaneous nephrolithotomy (PCNL), ultramini-PCNL, and micro-PCNL, have been developed recently. The aim of this meta-analysis was to compare the safety and efficacy of different tract sizes of MPCNL with retrograde intrarenal surgery (RIRS) in the management of kidney stones. MATERIALS AND METHODS:We searched PubMed, Embase, and Web of Science to identify case-control trials and randomized controlled trials, which evaluated MPCNL vs RIRS before February 2017. Two reviewers independently evaluated the methodologic quality of the included studies, and the disagreements were solved by discussion. Meta-analysis was performed with Review Manager version 5.3 software. RESULTS:Fourteen publications involving 1279 patients were included. Mini-PCNL provided a significantly higher stone-free rate (SFR; odds ratio [OR] OR 1.66; p = 0.005), especially for lower pole renal stones (OR 2.65; p = 0.003), but brought longer hospital stay (weighted mean difference [WMD] 1.23; p = 0.0001) and larger hemoglobin drop (WMD 0.77; p < 0.00001). There were no statistically significant differences between mini-PCNL and RIRS in the complications (OR 0.77; p = 0.23) and operative time (WMD: -6.52; p = 0.42). For ultramini-PCNL and micro-PCNL, the safety and efficacy were similar to RIRS. CONCLUSIONS:Mini-PCNL offers a significantly higher SFR than RIRS, for lower pole renal stones, the advantage of mini-PCNL is more obvious. However, RIRS is associated with shorter hospital stay and less hemoglobin drop. For ultramini-PCNL and micro-PCNL, tract size is smaller than mini-PCNL, and the SFR is similar to RIRS. In terms of the evidence at present, we recommend mini-PCNL for patients focusing more on the high SFR.

Our recent studies observed that trientine (TETA), a copper chelator, is capable of redistributing copper from plasma to the heart, leading to regression of cardiac fibrosis in rat model of pressure overload‐induced heart hypertrophy. The present study was undertaken to explore possible mechanisms by which copper repletion reverses cardiac fibrosis. Adult male Sprague‐Dawley rats were subjected to ascending aortic constriction (AAC) to induce pathological cardiac hypertrophy. Four months after the operation, cardiac hypertrophy along with fibrosis was fully developed as determined by pathological examination and Sirius red staining. At the same time, TETA at a dose of 4.38 mg/kg, twice a day, was administered orally for six weeks. At the end of the experiment, the expression and crosslinking of type I and III collagens were determined respectively by immunohistochemistry and Sircol collagen assay. Western blot was performed to detect the expressions of lysyl oxidase (LOX), MMP‐2 and MMP‐9. The results showed that the content and crosslinking of type I and III collagens were both significantly decreased after TETA treatment. The expression of MMP‐2 was up‐regulated, but the expressions of MMP‐9 and LOX were not changed. The data thus demonstrated that the reversal of cardiac fibrosis by TETA‐induced copper repletion is related at least in part to an enhanced collagen degradation process.Support or Funding InformationThis study is supported by National Science Foundation of China (81230004 and 81300109).