Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

Yuan, Deqiang; Chu, Jiapeng; Lin, Hui; Zhu, Guoqi; Qian, Jun; Yu, Yunan; Yao, Tongqing; Fan, Ping; Chen, Fei; Liu, Xuebo

doi:10.3389/fcvm.2022.1109445

Cited by 33 publications

(23 citation statements)

References 136 publications

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“…Homocysteine was observed as a specifically perturbed metabolite in female mice at the 1-month time point. Homocysteine has been implicated in oxidative stress and has been found to correlate with cardiovascular disease [42][43][44]. Altogether, our findings suggest that sex plays a significant role in the response to IR.…”

Section: Discussionsupporting

confidence: 61%

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction

Bansal

Sridharan

et al. 2023

Metabolites

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Survivors of acute radiation exposures are likely to experience delayed effects that manifest as injury in late-responding organs such as the heart. Noninvasive indicators of radiation-induced cardiac dysfunction are important in the prediction and diagnosis of this disease. In this study, we aimed to identify urinary metabolites indicative of radiation-induced cardiac damage by analyzing previously collected urine samples from a published study. The samples were collected from male and female wild-type (C57BL/6N) and transgenic mice constitutively expressing Activated Protein C (APCHi), a circulating protein with potential cardiac protective properties, that were exposed to 9.5 Gy of γ-rays. We utilized LC-MS-based metabolomics and lipidomics for the analysis of urine samples collected at 24 h, 1 week, 1 month, 3 months, and 6 months post-irradiation. Radiation caused perturbations in the TCA cycle, glycosphingolipid metabolism, fatty acid oxidation, purine catabolism, and amino acid metabolites, which were more prominent in wild-type (WT) mice compared to APCHi mice, suggesting a differential response between the two genotypes. After combining genotypes and sexes, we identified a multi-analyte urinary panel at early post-irradiation time points that predicted heart dysfunction using a logistic regression model with a discovery validation study design. These studies demonstrate the utility of a molecular phenotyping approach to develop a urinary biomarker panel predictive of delayed effects of ionizing radiation. It is important to note that no live mice were used or assessed in this study; instead, we focused solely on analyzing previously collected urine samples.

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Section: Discussionsupporting

confidence: 61%

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction

Bansal

Sridharan

et al. 2023

Metabolites

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“…Numerous other biomarkers have also been shown to increase in atherosclerosis. Elevated homocysteine levels (>12 μmol/L) have been shown to predict the progression of coronary plaque burden [ 100 ]. Furthermore, plasma amyloid-β (1–40) (Aβ40) has been associated with the presence of subclinical CAD in individuals without clinically overt CAD [ 101 , 102 ], arterial stiffness progression in young healthy individuals, as well as with cardiovascular mortality and MACE in patients with CAD [ 103 ].…”

Section: Identifying the “Vulnerable Patient”mentioning

confidence: 99%

Current Toolset in Predicting Acute Coronary Thrombotic Events: The “Vulnerable Plaque” in a “Vulnerable Patient” Concept

Emfietzoglou

Mavrogiannis

Stamatelopoulos

et al. 2023

Life

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Despite major advances in pharmacotherapy and interventional procedures, coronary artery disease (CAD) remains a principal cause of morbidity and mortality worldwide. Invasive coronary imaging along with the computation of hemodynamic forces, primarily endothelial shear stress and plaque structural stress, have enabled a comprehensive identification of atherosclerotic plaque components, providing a unique insight into the understanding of plaque vulnerability and progression, which may help guide patient treatment. However, the invasive-only approach to CAD has failed to show high predictive value. Meanwhile, it is becoming increasingly evident that along with the “vulnerable plaque”, the presence of a “vulnerable patient” state is also necessary to precipitate an acute coronary thrombotic event. Non-invasive imaging techniques have also evolved, providing new opportunities for the identification of high-risk plaques, the study of atherosclerosis in asymptomatic individuals, and general population screening. Additionally, risk stratification scores, circulating biomarkers, immunology, and genetics also complete the armamentarium of a broader “vulnerable plaque and patient” concept approach. In the current review article, the invasive and non-invasive modalities used for the detection of high-risk plaques in patients with CAD are summarized and critically appraised. The challenges of the vulnerable plaque concept are also discussed, highlighting the need to shift towards a more interdisciplinary approach that can identify the “vulnerable plaque” in a “vulnerable patient”.

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“…Agonist sensitivity (pEC50) and % maximum response (Rmax) of endothelium-dependent vasodilator, acetylcholine and endothelium-independent vasodilator sodium nitroprusside (SNP), in isolated aorta from SD rats treated with different concentration of Hcy (100 µM, 300 µM, 500 µM), 500 µM Hcy cotreated with TQ (0.1 µM, 1 µM, and 10 µM), 20 Homocysteine has been reported to reduce the endothelial cells viability during endothelial cells dysfunction [34][35][36]. Figure 2a shows HUVECS treated with Hcy has a reduction in cell viability in a concentration-dependent manner compared to control, with 10 mM of Hcy being the most effective concentration that caused apoptosis compared to control.…”

Section: Tablementioning

confidence: 99%

Thymoquinone reverses homocysteine-induced endothelial dysfunction via inhibition of ER-stress induced oxidative stress pathway

Sofiullah

Murugan

Muid

et al. 2023

Preprint

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Hyperhomocysteinemia has been linked to an increased risk of cardiovascular diseases. High levels of homocysteine (Hcy) promote endoplasmic reticulum (ER) stress that can increase reactive oxygen species (ROS), leading to endothelial dysfunction. Thymoquinone (TQ) is the major active ingredient in Nigella sativa seeds volatile oil and is shown to have a cardioprotective effect. However, no study evaluated the effect of TQ against Hcy-induced endothelial dysfunction. Thus, this study aims to investigate the effects and mechanisms of TQ in reversing Hcy-induced endothelial dysfunction. Isolated aorta from male Sprague-Dawley (SD) rats incubated with Hcy (500 µM) and co-treated with or without TQ (0.1 µM, 1 µM, and 10 µM), 20 µM TUDCA, 100 µM Apocynin or 1 mM Tempol in organ bath to study the vascular function. Additionally, human umbilical vein endothelial cells (HUVECs) were incubated with Hcy (10 mM) and various concentrations of TQ (1 and 10 𝜇M), Tempol (100 𝜇M), Apocynin (100 𝜇M), TUDCA (100 𝜇M) or H2O2 (0.25 mM) to evaluate the cell viability by using a phase contrast microscope and dye exclusion assay. Involvement of ER stress pathway, ROS and NO bioavailability were accessed via immunoassay and fluorescent staining respectively. Molecular docking was performed to evaluate the binding affinity of TQ to GRP78. Our results revealed that Hcy impaired endothelium-dependant relaxation in isolated aorta and induced apoptosis in HUVECs. These effects were reversed by TQ, TUDCA, tempol and apocynin. Treatment with TQ (10𝜇M) also reduced ROS level, improved NO bioavailability as well reduced GRP78 and NOX4 protein in HUVECs. Result from the molecular docking study showed that TQ could bind well to GRP78 through hydrogen bond and hydrophobic interaction with the amino acid at GRP78 ATP binding pocket. Taken together, the present results suggest that TQ preserved endothelial function in rat aorta and reduced apoptosis of HUVECs induced by Hcy through the inhibition of ER stress-mediated ROS and eNOS uncoupling.

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Mechanism of homocysteine-mediated endothelial injury and its consequences for atherosclerosis

Cited by 33 publications

References 136 publications

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction

Urinary Metabolomics for the Prediction of Radiation-Induced Cardiac Dysfunction

Current Toolset in Predicting Acute Coronary Thrombotic Events: The “Vulnerable Plaque” in a “Vulnerable Patient” Concept

Thymoquinone reverses homocysteine-induced endothelial dysfunction via inhibition of ER-stress induced oxidative stress pathway

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