Recently, cuproptosis has been demonstrated to be a new non-apototic cell death mode that is characterized by copper dependence and the regulation of mitochondrial respiration. Cuproptosis is distinct from known cell death modes such as apoptosis, necrosis, pyroptosis, or ferroptosis. Excessive copper induces cuproptosis by promoting protein toxic stress reactions via copper-dependent anomalous oligomerization of lipoylation proteins in the tricarboxylic acid (TCA) cycle and reducing iron-sulfur cluster protein levels. Ferredoxin1 (FDX1) promotes dihydrolipoyl transacetylase (DLAT) lipoacylation and abates iron-sulfur cluster proteins by reducing Cu2+ to Cu+, inducing cell death. Copper homeostasis depends on the copper transporter, and disturbances to this homeostasis cause cuproptosis. Recent evidence has shown that cuproptosis plays a significant role in the occurrence and development of many cardiovascular diseases, such as myocardial ischemia/reperfusion (I/R) injury, heart failure, atherosclerosis, and arrhythmias. Copper chelators, such as ammonium tetrathiomolybdate(VI) and DL-Penicillamine, may ease the above cardiovascular diseases by inhibiting the cuproptosis pathway. Oxidative phosphorylation inhibitors may inhibit cuproptosis by inhibiting protein stress response. In conclusion, cuproptosis plays an essential role in cardiovascular disease pathogenesis. Inhibition of cardiovascular cuproptosis is expected to become a potential treatment. Here, we will thoroughly review the molecular mechanisms involved in cuproptosis and its significance in cardiovascular disease. 

The molecular mechanisms of cuproptosis and its relevance to cardiovascular disease.

Copper (Cu) homeostasis is gaining increasing attention in human health as both Cu overload and deficiency evokes pathological changes including cardiovascular diseases (CVDs). Cu supplementation, nanocarriers, and chelators have all exhibited therapeutic promise in some human diseases, although how Cu dyshomeostasis and cuproptosis, a novel form of regulated cell death, contribute to CVD pathology remains elusive. Here, we discuss Cu dyshomeostasis and the potential role of cuproptosis in various CVDs. We evaluate underlying cellular mechanisms, aiming to provide some insights regarding the utility of targeting Cu dyshomeostasis and cuproptosis as a novel strategy in the management of CVDs. 

Copper homeostasis and cuproptosis in cardiovascular disease therapeutics.

Atherogenic index of plasma (AIP) represents a novel marker in the current era of cardiovascular diseases. In this meta-analysis, we aimed to evaluate the association of AIP with cardiovascular prognosis in patients with coronary artery disease (CAD).PubMed, Scopus, and Web of Science databases were searched from inception through 2024. The primary outcome was major cardiovascular events (MACE). The secondary outcomes included all-causes death, cardiovascular death, myocardial infarction (MI), stroke, revascularization, and no-reflow phenomenon. AIP was determined by taking the logarithm of the ratio of triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C). The data analysis was represented using the risk ratio (RR) along with a 95% confidence interval (CI).Sixteen studies with a total number of 20,833 patients met the eligible criteria. The pooled-analysis showed a significant increased risk of MACE in the highest AIP group compared with the lowest AIP group (RR = 1.63; 95% CI, 1.44-1.85; P < 0.001). A similar result was observed when AIP was regarded as a continuous variable (RR = 1.54; 95% CI, 1.30-1.83; P < 0.001). Besides, elevated AIP was associated with increased risk of cardiovascular death (RR = 1.79; 95% CI, 1.09-2.78; P = 0.02), MI (RR = 2.21; 95% CI, 1.55-3.13; P < 0.001), revascularization (RR = 1.62; 95% CI, 1.34-1.97; P < 0.001), no-reflow phenomenon (RR = 3.12 95% CI, 1.09-8.96; P = 0.034), and stent thrombosis (RR = 13.46; 95%CI, 1.39-129.02; P = 0.025). However, AIP was not significantly associated with the risk of all-causes death and stroke among patients with CAD.The results of this study demonstrated that increased AIP is an independent prognostic factors in patients with CAD. Further research is warranted to elucidate the potential development of targeted interventions to modify AIP levels and improve patient outcomes. 

The association of atherogenic index of plasma with cardiovascular outcomes in patients with coronary artery disease: A systematic review and meta-analysis

The sustenance of human life activities depends on copper, which also serves as a crucial factor for vital enzymes. Under typical circumstances, active homeostatic mechanisms keep the intracellular copper ion concentration low. Excess copper ions cause excessive cellular respiration, which causes cytotoxicity and cell death as levels steadily rise above a threshold. It is a novel cell death that depends on mitochondrial respiration, copper ions, and regulation. Cuproptosis is now understood to play a role in several pathogenic processes, including inflammation, oxidative stress, and apoptosis. Copper death is a type of regulatory cell death(RCD).Numerous diseases are correlated with the development of copper homeostasis imbalances. One of the most popular areas of study in the field of cancer is cuproptosis. It has been discovered that cancer angiogenesis, proliferation, growth, and metastasis are all correlated with accumulation of copper ions. Copper ion concentrations can serve as a crucial marker for cancer development. In order to serve as a reference for clinical research on the product, diagnosis, and treatment of cancer, this paper covers the function of copper ion homeostasis imbalance in malignant cancers and related molecular pathways.

Cuproptosis: emerging biomarkers and potential therapeutics in cancers

Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings.

Interplay of Ferroptosis and Cuproptosis in Cancer: Dissecting Metal-Driven Mechanisms for Therapeutic Potentials

Background and Objective Heart failure (HF) is a global public health problem with high morbidity, readmission, and mortality rates. The central mediators of cardiomyocyte survival and death are mitochondria. Mitochondria are a key therapeutic target for HF and are closely involved in the pathophysiological process of HF. A recent study proposes that cuproptosis, a novel cell death mechanism, is closely related to mitochondrial respiration. Therefore, this study aims to explore the link between cuproptosis and HF, and to find novel therapeutic targets and treatments for HF. Methods A literature search (up to April 2022) was conducted through PubMed database, and the search range was limited to publications in English. After further literature search and screening, we found that we are currently the first study to explore the association between HF and cuproptosis. Key Content and Findings Research has found that mitochondria are a key therapeutic target in HF and are involved in the pathophysiological processes of energy metabolism, oxidative stress, calcium regulation, and cell death in HF. The micronutrient copper is involved in regulating mitochondrial biological processes, and high serum copper levels are significantly associated with HF. Copper overload affects mitochondrial function and exacerbates the development of HF. And cuproptosis induced by copper overload targeting lipoylated tricarboxylic acid cycle proteins, is closely related to mitochondrial respiration. Copper chelators not only treat HF but also partially rescue copper-mediated cell death. Copper binding to lipoylated components may be the reason for the hyperacetylation of mitochondrial proteins in HF. Ferredoxin 1 (FDX1) may be an upstream regulator of protein lipoylation and is closely related to cuproptosis. Conclusions This study demonstrates the important roles of mitochondria and micronutrient copper in HF. Cuproptosis may be involved in the pathophysiological process of HF and is responsible for the hyperacetylation of mitochondrial proteins in HF. Cuproptosis has the potential to be a novel therapeutic mechanism for HF, and FDX1 may be a key target for cuproptosis-based treatment of HF. This study provides a new research direction for the treatment of HF and new ideas for the development of new drugs.

/pdf/cuproptosis-the-novel-therapeutic-mechanism-for-heart-2clnyqhx.pdf

Cuproptosis, the novel therapeutic mechanism for heart failure: a narrative review

Abnormal glycemic variability is common in the intensive care unit (ICU) and is associated with increased in-hospital mortality and major adverse cardiovascular events, but little is known about whether adverse outcomes are partly mediated by ventricular arrhythmias (VA). We aimed to explore the association between glycemic variability and VA in the ICU and whether VA related to glycemic variability mediate the increased risk of in-hospital death.We extracted all measurements of blood glucose during the ICU stay from The Medical Information Mart for Intensive Care IV (MIMIC-IV) database version 2.0. Glycemic variability was expressed by the coefficient of variation (CV), which was calculated by the ratio of standard deviation (SD) and average blood glucose values. The outcomes included the incidence of VA and in-hospital death. The KHB (Karlson, KB & Holm, A) is a method to analyze the mediation effect for nonlinear models, which was used to decompose the total effect of glycemic variability on in-hospital death into a direct and VA-mediated indirect effect.Finally, 17,756 ICU patients with a median age of 64 years were enrolled; 47.2% of them were male, 64.0% were white, and 17.8% were admitted to the cardiac ICU. The total incidence of VA and in-hospital death were 10.6% and 12.8%, respectively. In the adjusted logistic model, each unit increase in log-transformed CV was associated with a 21% increased risk of VA (OR 1.21, 95% CI: 1.11-1.31) and a 30% increased risk (OR 1.30, 95% CI: 1.20-1.41) of in-hospital death. A total of 3.85% of the effect of glycemic variability on in-hospital death was related to the increased risk of VA.High glycemic variability was an independent risk factor for in-hospital death in ICU patients, and the effect was caused in part by an increased risk of VA. 

Glycemic variability and in-hospital death of critically ill patients and the role of ventricular arrhythmias

The atherogenic index of plasma (AIP) is a novel biomarker associated with atherosclerosis, and an important risk factor for atherosclerosis, but its relation with cardiovascular prognosis in prediabetic patients with unstable angina pectoris (UAP) is still uncertain.This study included 1096 prediabetic patients with UAP who were subjected to follow-up for a maximum of 30 months, with cardiac death, refractory angina, and non-fatal myocardial infarction (MI) being the primary cardiovascular endpoints.A significantly increased AIP was observed for the group with primary cardiovascular endpoints. Kaplan-Meier curves corresponding to these endpoints revealed pronounced differences between these two AIP groups (Log-rank P < 0.001). Multivariate Cox proportional hazards analyses highlighted AIP as being independent related to this primary endpoint (HR 1.308, 95% CI: 1.213-1.412, P < 0.001). AIP addition to the baseline risk model improved the prediction of the primary endpoint (AUC: baseline model, 0.622, vs. baseline model + AIP, 0.739, P < 0.001).AIP could be used to predict cardiovascular events in prediabetic individuals with UAP. 

The relation between atherogenic index of plasma and cardiovascular outcomes in prediabetic individuals with unstable angina pectoris

Background: Measuring glycosylated hemoglobin (HbA 1c ) is a simple way to assess patients with prediabetes or diabetes mellitus. It has been shown that HbA 1c level predicts prognosis in patients with coronary artery disease (CAD) and the incidence of diabetes mellitus. However, the prognostic significance of HbA 1c level in Asian patients with prediabetes and CAD is not yet clear. Our study aimed to determine the relationship between HbA 1c level and major adverse cardiovascular events (MACE) in patients with prediabetes and CAD. Methods: We enrolled 1367 patients with prediabetes and CAD in the final analysis, and grouped them according to the HbA 1c level. Primary end points included nonfatal myocardial infarction, hospitalization for unstable angina, and ischemia-driven revascularization. Cox proportional-hazards regression analysis was used to determine the relationship between HbA 1c level and MACE after our accounting for confounding factors. Results: A total of 1367 patients (age 58.8 ± 10.3 years; 71.6% men) were included. During 43 months of follow-up, 197 patients experienced at least one primary end point event. Multivariate Cox proportional-hazards regression analysis showed in comparison of HbA 1c levels that the hazard ratio for primary end points was 4.110, with a 95% confidence interval of 2.097–6.011 (P < 0.001). Conclusions: HbA1c level positively correlated with MACE, demonstrating it is a valuable indicator for independently predicting MACE in Asian patients with prediabetes and CAD. stent implantation, balloon use, number of stents, and uric acid level.

Prognostic Significance of HbA 1c Level in Asian Patients with Prediabetes and Coronary Artery Disease

Background: Serum uric acid (SUA) levels has been considered a possible risk factor for coronary artery disease (CAD) for many years. Since SUA levels are greatly affected by medications, diet, and metabolism, the association between SUA and CAD has been controversial for centuries. While, the state of hyperuricemia (HUA) has been proven to have a negative impact on CAD in previous studies, there are still few clinical and epidemiological studies of HUA in CAD. In particular, evidence of this association is limited in postmenopausal women. This study explored the influence of SUA levels and HUA on CAD in this demographic group. Methods: In total, 5435 postmenopausal women were allocated to either a non-CAD group (n = 2021) or a CAD group (n = 3414). Regression analyses, including generalized linear models (GLM), correlation analysis, comparison between stratified groups, and analysis by use of diuretics were carried out on data obtained in this study. Results: SUA and HUA were found to associate significantly with CAD by univariate logistic regression analysis. In addition, GLM showed nonlinear response of CAD probability with increasing level of SUA. In multivariate analysis, we found that SUA and HUA were independently related to CAD. Correlation analysis showed that SUA and HUA both correlated positively with CAD (p &lt; 0.001). By comparing the stratified age groups, we found that the differences among the age groups were significant (p &lt; 0.05). Conclusions: SUA and HUA were shown to be independently associated with CAD among postmenopausal women. 

Serum Uric Acid and Hyperuricemia Associate with Coronary Artery Disease among Postmenopausal Women

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