The Molecular Mechanisms of Defective Copper Metabolism in Diabetic Cardiomyopathy.
Oxidative medicine and cellular longevity
Copper is an essential trace metal element that significantly affects human physiology and pathology by regulating various important biological processes, including mitochondrial oxidative phosphorylation, connective tissue crosslinking, and antioxidant defense. Copper level has been proved to be closely related to the morbidity and mortality of cardiovascular diseases such as atherosclerosis, heart failure, and diabetic cardiomyopathy (DCM). Copper deficiency can induce cardiac hypertrophy and aggravate cardiomyopathy, while copper excess can mediate various types of cell death, such as autophagy, apoptosis, cuproptosis, pyroptosis, and cardiac hypertrophy and fibrosis. Both copper excess and copper deficiency lead to redox imbalance, activate inflammatory response, and aggravate diabetic cardiomyopathy. This defective copper metabolism suggests a specific metabolic pattern of copper in diabetes and a specific role in the pathogenesis and progression of DCM. This review is aimed at providing a timely summary of the effects of defective copper homeostasis on DCM and discussing potential underlying molecular mechanisms.
10.1155/2022/5418376
Sleep restriction exacerbates cardiac dysfunction in diabetic mice by causing cardiomyocyte death and fibrosis through mitochondrial damage.
Cell death discovery
Diabetic cardiomyopathy (DCM) is a cardiovascular complication of diabetes mellitus with a poor prognosis and is the leading cause of death in diabetic patients. Sleep deficiency is not only recognized as an important risk factor for the development of type 2 DM, but is also associated with increased morbidity and mortality of cardiovascular disease. The underlying role and mechanisms of sleep restriction (SR) in DCM are far from clear. The KK/Upj-Ay mouse model of T2 DM was used as a study subject, and the small animal ultrasound imaging system was used to detect the function of the heart; immunopathological staining was used to clarify the histo-structural pathological alterations of the heart; and TUNEL staining, qPCR, transmission electron microscopy (TEM), and ELISA kits were used to detect apoptosis, oxidative stress, inflammation, and mitochondrial damage, and related molecular alterations. SR led to a significant increase in mortality, cardiac hypertrophy, necrosis, glycogen deposition and fibrosis further deteriorated in DM KK mice. SR increased cardiomyocyte death in KK mice through the Bax/Bcl2 pathway. In addition to this, SR not only exacerbated the inflammatory response, but also aggravated mitochondrial damage and promoted oxidative stress in KK mice through the PRDM16-PGC-1α pathway. Overall, SR exacerbates structural alterations and dysfunction through inflammation, oxidative stress, and apoptosis in DM KK mice, increasing the risk of death. Clinicians and diabetic patients are prompted to pay attention to sleep habits to avoid accelerating the transition of DCM to heart failure and inducing death due to poor sleep habits.
10.1038/s41420-024-02214-w
Catecholamine treatment induces reversible heart injury and cardiomyocyte gene expression.
Intensive care medicine experimental
BACKGROUND:Catecholamines are commonly used as therapeutic drugs in intensive care medicine to maintain sufficient organ perfusion during shock. However, excessive or sustained adrenergic activation drives detrimental cardiac remodeling and may lead to heart failure. Whether catecholamine treatment in absence of heart failure causes persistent cardiac injury, is uncertain. In this experimental study, we assessed the course of cardiac remodeling and recovery during and after prolonged catecholamine treatment and investigated the molecular mechanisms involved. RESULTS:C57BL/6N wild-type mice were assigned to 14 days catecholamine treatment with isoprenaline and phenylephrine (IsoPE), treatment with IsoPE and subsequent recovery, or healthy control groups. IsoPE improved left ventricular contractility but caused substantial cardiac fibrosis and hypertrophy. However, after discontinuation of catecholamine treatment, these alterations were largely reversible. To uncover the molecular mechanisms involved, we performed RNA sequencing from isolated cardiomyocyte nuclei. IsoPE treatment resulted in a transient upregulation of genes related to extracellular matrix formation and transforming growth factor signaling. While components of adrenergic receptor signaling were downregulated during catecholamine treatment, we observed an upregulation of endothelin-1 and its receptors in cardiomyocytes, indicating crosstalk between both signaling pathways. To follow this finding, we treated mice with endothelin-1. Compared to IsoPE, treatment with endothelin-1 induced minor but longer lasting changes in cardiomyocyte gene expression. DNA methylation-guided analysis of enhancer regions identified immediate early transcription factors such as AP-1 family members Jun and Fos as key drivers of pathological gene expression following catecholamine treatment. CONCLUSIONS:The results from this study show that prolonged catecholamine exposure induces adverse cardiac remodeling and gene expression before the onset of left ventricular dysfunction which has implications for clinical practice. The observed changes depend on the type of stimulus and are largely reversible after discontinuation of catecholamine treatment. Crosstalk with endothelin signaling and the downstream transcription factors identified in this study provide new opportunities for more targeted therapeutic approaches that may help to separate desired from undesired effects of catecholamine treatment.
10.1186/s40635-024-00632-9
Copper homeostasis and copper-induced cell death in the pathogenesis of cardiovascular disease and therapeutic strategies.
Cell death & disease
Copper is a vital mineral, and an optimal amount of copper is required to support normal physiologic processes in various systems, including the cardiovascular system. Over the past few decades, copper-induced cell death, named cuproptosis, has become increasingly recognized as an important process mediating the pathogenesis and progression of cardiovascular disease (CVD), including atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. Therefore, an in-depth understanding of the regulatory mechanisms of cuproptosis in CVD may be useful for improving CVD management. Here, we review the relationship between copper homeostasis and cuproptosis-related pathways in CVD, as well as therapeutic strategies addressing copper-induced cell death in CVD.
10.1038/s41419-023-05639-w
Transcriptomic profiling and risk assessment in bladder cancer: Insights from copper death-related genes.
Cellular signalling
BACKGROUND:The study aimed to investigate the role of copper death-related genes (CRGs) in bladder cancer (BC) for improved prognosis assessment. METHODS:Multi-omics techniques were utilized to analyze CRG expression in BC tissues from TCGA and GEO databases. Consensus clustering categorized patients into molecular subtypes based on clinical characteristics and immune cell infiltration. RESULTS:An innovative risk assessment model identified eight critical genes associated with BC risk. In vitro and in vivo experiments validated LIPT1's significant impact on copper-induced cell death, proliferation, migration, and invasion in BC. CONCLUSION:This multi-omics analysis elucidates the pivotal role of CRGs in BC progression, suggesting enhanced risk assessment through molecular subtype categorization and identification of key genes like LIPT1. Insights into these mechanisms offer the potential for improved diagnosis and treatment strategies for BC patients.
10.1016/j.cellsig.2024.111237
Bioinformatics analysis of copper death gene in diabetic immune infiltration.
Medicine
BACKGROUND:Copper plays an important role in the human body and is potentially related to the development of diabetes. The mechanism of copper death gene regulating immune infiltration in diabetes has not been studied. METHODS:Download microarray data from healthy normal and diabetic patients from the GEO database. The identification of differentially expressed genes (DEGs) was analyzed by gene enrichment. Using String online database and Cytoscape software to interact with the protein interaction network and make visual analysis. Using Wilcox analyze the correlation between the copoer death gene and diabetic mellitus. Analysis of the correlation between immune penetration cells and functions, and the difference between the diabetes group and the control group, screening the copper death gene associated with diabetes, and predicting the upper top of microRNA (miRNA) through the Funrich software. RESULTS:According to the identification of differential genes in 25 samples of GSE25724 and GSE95849 data sets, 328 differential genes were identified by consensus, including 190 up-regulated genes and 138 down-regulated genes (log2FC = 2, P < .01). KEGG results showed that neurodegeneration-multiple disease pathways were most significantly upregulated, followed by Huntington disease. According to Cytohubba, the TOP10 genes HCK, FPR1, MNDA, AQP9, TLR8, CXCR1, CSF3R, VNN2, TLR4, and CCR5 are down-regulated genes, which are mostly enriched in neutrophils. Immunoinfiltration-related heat maps show that Macrophage was strongly positively correlated with Activated dendritic cell, Mast cell, Neutrophil, and Regulatory T cell showed a strong positive correlation. Neutrophil was strongly positively correlated with Activated dendritic cell, Mast cell, and Regulatory T cell. Differential analysis of immune infiltration showed that Neutroph, Mast cell, Activated B cell, Macrophage and Eosinophil were significantly increased in the diabetic group. Central memory CD4 T cell (P < .001), Plasmacytoid dendritic cell, Immature dendritic cell, and Central memory CD8 T cell, etal were significantly decreased. DBT, SLC31A1, ATP7A, LIAS, ATP7B, PDHA1, DLST, PDHB, GCSH, LIPT1, DLD, FDX1, and DLAT genes were significantly associated with one or more cells and their functions in immune invasion. Forty-one miRNA. CONCLUSIONS:Copper death is closely related to the occurrence of diabetes. Copper death genes may play an important role in the immune infiltration of diabetes.
10.1097/MD.0000000000035241