Association of Blood Copper With the Subclinical Carotid Atherosclerosis: An Observational Study.

BACKGROUND: Copper exposure is reported to be associated with increased risk of stroke. However, the association of copper exposure with subclinical carotid atherosclerosis remains unclear. METHODS AND RESULTS: This observational study included consecutive participants from Xinqiao Hospital between May 2020 and August 2021. Blood metals were measured using inductively coupled plasma mass spectrometry and carotid atherosclerosis was assessed using ultrasound. Modified Poisson regression was performed to evaluate the associations of copper and other metals with subclinical carotid plaque presence. Blood metals were analyzed as categorical according to the quartiles. Multivariable models were adjusted for age, sex, body mass index, education, smoking, drinking, hypertension, diabetes, dyslipidemia, estimated glomerular filtration rate, and coronary artery disease history. Bayesian Kernel Machine Regression was conducted to evaluate the overall association of metal mixture with subclinical carotid plaque presence. One thousand five hundred eighty-five participants were finally enrolled in our study, and carotid plaque was found in 1091 subjects. After adjusting for potential confounders, metal-progressively-adjusted models showed that blood copper was positively associated with subclinical carotid plaque (relative risk according to comparing quartile 4 to quartile 1 was 1.124 [1.021-1.238], relative risk according to per interquartile increment was 1.039 [1.008-1.071]). Blood cadmium and lead were also significantly associated with subclinical carotid plaque. Bayesian Kernel Machine Regression analyses suggested a synergistic effect of copper-cadmium-lead mixture on subclinical carotid plaque presence. CONCLUSIONS: Our findings identify copper as a novel risk factor of subclinical carotid atherosclerosis and show the potential synergistic proatherogenic effect of copper, cadmium, and lead mixture.

Association of multiple blood metals and systemic atherosclerosis: A cross-sectional study in the CAD population.

BACKGROUND: Coronary atherosclerotic disease (CAD) is often accompanied by peripheral atherosclerosis, resulting in a higher risk of ischemia and cardiovascular death. Exposure to metals is associated with atherosclerotic plaques at specific sites. However, less is known about the effects of mixed metals on systemic atherosclerotic burden in CAD patients. OBJECTIVES: To investigate the association of metal mixtures with systemic atherosclerotic burden in a CAD population. METHODS: A cross-sectional study including 1562 CAD patients from Southwest China was conducted. The levels of 10 blood metals were measured via inductively coupled plasma spectrometry. More than one vessel with a stenosis ≥50% vessel diameter was defined as CAD. Carotid and lower limb atherosclerosis was assessed by using ultrasound, and coronary atherosclerosis was quantified via arterial angiography. Systemic atherosclerosis was scored according to the presence or absence of lesions at the three sites and the total number of lesions. To investigate the combined impacts and interaction effects of metals, Bayesian kernel machine regression was used. Weighted quantile regression was used to identify the contributions of the metals. RESULTS: Significant overall associations of mixed metals with systemic atherosclerotic burden were found. These positive overall associations were mainly driven by Cd, Cu and Pb in systemic atherosclerosis. The main contributing factors were As and Cu for coronary atherosclerosis as well as Cd, Cu and Pb for carotid and lower limb atherosclerosis. Cd and Pb or Cr can interact, and Pb interacts with age, sex and alcohol. CONCLUSIONS: In CAD patients, exposure to combinations of metals was highly positively associated with systemic atherosclerotic burden. These significant trends were more pronounced in the peripheral arteries and carotid arteries. Controlling environmental metal exposure can contribute to reducing systemic atherosclerosis in CAD patients.

Cadmium exposure promotes ferroptosis by upregulating Heat Shock Protein 70 in vascular endothelial damage of zebrafish.

Cadmium (Cd) exposure is a risk factor for endothelial dysfunction and cardiovascular disease. Ferroptosis is a type of cell death that relies on lipid peroxidation. Whether ferroptosis acts in Cd-induced vascular endothelial damage and the underlying mechanisms remain unclear. Herein, we found that Cd resulted in ferroptosis of vascular endothelial cells (ECs) in vivo and in vitro. In the visualized zebrafish embryos, Cd accumulated in vascular ECs, ROS and lipid peroxidation levels were increased, and the oxidoreductase system was disturbed after exposure. Moreover, Cd decreased Gpx4 in ECs and caused smaller mitochondria with increased membrane density. Accompanied by ferroptosis, the number of ECs and the area of the caudal venous plexus in zebrafish embryos were reduced, and the survival rate of HUVECs decreased. These effects were partially reversed by ferrostatin-1 and aggravated by erastin. Mechanistically, an excessive increase in Heat Shock Protein 70 (Hsp70) was identified by transcriptomics after Cd exposure. Inhibition of Hsp70 by VER-155008 or siRNA ameliorated Cd-induced ferroptosis, thereby alleviating endothelial injury. Furthermore, Hsp70 regulated Cd-induced ferroptosis by targeting multiple targets, including Gpx4, Fth1, Nrf2 and Acsl4. Our findings provide a new approach to investigating the endothelial damage of Cd and indicate that regulation of Hsp70 is an important target for alleviating this process.

Upregulation of mitochondrial calcium uniporter contributes to paraquat-induced neuropathology linked to Parkinson's disease via imbalanced OPA1 processing.

Paraquat (PQ) is the most widely used herbicide in agriculture worldwide and has been considered a high-risk environmental factor for Parkinson's disease (PD). Chronic PQ exposure selectively induces dopaminergic neuron loss, the hallmark pathologic feature of PD, resulting in Parkinson-like movement disorders. However, the underlying mechanisms remain unclear. Here, we demonstrated that repetitive PQ exposure caused dopaminergic neuron loss, dopamine deficiency and motor deficits dose-dependently in mice. Accordingly, mitochondrial calcium uniporter (MCU) was highly expressed in PQ-exposed mice and neuronal cells. Importantly, MCU knockout (KO) effectively rescued PQ-induced dopaminergic neuron loss and motor deficits in mice. Genetic and pharmacological inhibition of MCU alleviated PQ-induced mitochondrial dysfunction and neuronal death in vitro. Mechanistically, PQ exposure triggered mitochondrial fragmentation via imbalance of the optic atrophy 1 (OPA1) processing manifested by cleavage of L-OPA1 to S-OPA1, which was reversed by inhibition of MCU. Notably, the upregulation of MCU was mediated by miR-129-1-3p posttranscriptionally, and overexpression of miR-129-1-3p could rebalance OPA1 processing and attenuate mitochondrial dysfunction and neuronal death induced by PQ exposure. Consequently, our work uncovers an essential role of MCU and a novel molecular mechanism, miR-MCU-OPA1, in PQ-induced pathogenesis of PD, providing a potential target and strategy for environmental neurotoxins-induced PD treatment.

MCU Upregulation Overactivates Mitophagy by Promoting VDAC1 Dimerization and Ubiquitination in the Hepatotoxicity of Cadmium.

Cadmium (Cd) is a high-risk pathogenic toxin for hepatic diseases. Excessive mitophagy is a hallmark in Cd-induced hepatotoxicity. However, the underlying mechanism remains obscure. Mitochondrial calcium uniporter (MCU) is a key regulator for mitochondrial and cellular homeostasis. Here, Cd exposure upregulated MCU expression and increased mitochondrial Ca2+ uptake are found. MCU inhibition through siRNA or by Ru360 significantly attenuates Cd-induced excessive mitophagy, thereby rescues mitochondrial dysfunction and increases hepatocyte viability. Heterozygous MCU knockout mice exhibit improved liver function, ameliorated pathological damage, less mitochondrial fragmentation, and mitophagy after Cd exposure. Mechanistically, Cd upregulates MCU expression through phosphorylation activation of cAMP-response element binding protein at Ser133(CREBS133 ) and subsequent binding of MCU promoter at the TGAGGTCT, ACGTCA, and CTCCGTGATGTA regions, leading to increased MCU gene transcription. The upregulated MCU intensively interacts with voltage-dependent anion-selective channel protein 1 (VDAC1), enhances its dimerization and ubiquitination, resulting in excessive mitophagy. This study reveals a novel mechanism, through which Cd upregulates MCU to enhance mitophagy and hepatotoxicity.

Independent association of blood cadmium with subclinical lower extremity atherosclerosis: An observational study based on dose-response analysis.

BACKGROUND: Atherosclerosis is an increasingly public health issue globally. Previous studies have showed a causal link between heavy metal exposure and atherosclerosis. However, the association of cadmium concentration with subclinical lower extremity atherosclerosis (SLEA) remains unclear. AIMS: To investigate the association of blood cadmium with SLEA and its extent, and further analyze the potential dose-response relationship. METHODS: Blood cadmium concentration was measured using inductively coupled plasma mass spectrometry. SLEA and its extent were assessed by ultrasound diagnosis system. Multivariate models were applied to evaluate the association of blood cadmium with SLEA and its extent. Restricted cubic splines were performed to explore the potential dose-response relationship. RESULTS: This observational study consisted of 1664 participants from cardiovascular outpatient, with an average age of 62.4 years and 1218 (73.2%) men. When blood cadmium was included as a categorical variable in multivariate models, logistic regression analysis showed that high quartile in blood cadmium was an independent risk factor of SLEA (OR = 2.704, 95%CI 1.866-3.919). After log-transformed for SLEA extent parameters, linear regression analysis indicated that high quartile in blood cadmium was significantly associated with higher Crouse score (GMR = 1.21, 95%CI 1.15-1.28), plaque maximum thickness (GMR = 1.13, 95%CI 1.09-1.18) and diseased vessel count (GMR = 1.14, 95%CI 1.10-1.19), respectively. When blood cadmium was used as a continuous variable in restricted cubic splines, the dose-response relationship presented a positive progression in SLEA (P = 0.302), plaque maximum thickness (P = 0.145) and diseased vessel count (P = 0.055) apparently that did not deviate from linearity. CONCLUSIONS: Blood cadmium exhibited an independent association with SLEA, and this dose-response relationship was progressive without significant departure from linearity.

Promoter variation in a homeobox gene, CpDll, is associated with deeply lobed leaf in Cucurbita pepo L.

KEY MESSAGE: CpDll, encoding an HD-Zip I transcription factor, positively regulates formation of deeply lobed leaf shape in zucchini, Cucurbita pepo, which is associated with sequence variation in its promoter region. Leaf shape is an important horticultural trait in zucchini (Cucurbita pepo L.). Deeply lobed leaves have potential advantages for high-density planting and hybrid production. However, little is known about the molecular basis of deeply lobed leaf formation in this important vegetable crop. Here, we conducted QTL analysis and fine mapping of the deeply lobed leaf (CpDll) locus using recombinant inbred lines and large F2 populations developed from crosses between the deeply lobed leaf HM-S2, and entire leaf Jin-GL parental lines. We show that CpDll exhibited incomplete dominance for the deeply lobed leaf shape in HM-S2. Map-based cloning provided evidence that CpCll encodes a type I homeodomain (HD)- and Leu zipper (Zip) element-containing transcription factor. Sequence analysis between HM-S2 and Jin-GL revealed no sequence variations in the coding sequences, whereas a number of variations were identified in the promoter region between them. DUAL-LUC assays revealed significantly stronger promoter activity in HM-S2 than that in Jin-GL. There was also significantly higher expression of CpDll in the leaf base of deeply lobed leaves of HM-S2 compared with entire leaf Jin-GL. Comparative analysis of CpDll gene homologs in nine cucurbit crop species (family Cucurbitaceae) revealed conservation in both structure and function of this gene in regulation of deeply lobed leaf formation. Our work provides new insights into the molecular basis of leaf lobe formation in pumpkin/squash and other cucurbit crops. This work also facilitates marker-assisted selection for leaf shape in zucchini breeding.