Relevance of plasma levels of free homocysteine and methionine as risk predictors for ischemic stroke in the young

Rudreshkumar, Kondapura Jayadevappa; Majumdar, Vijaya; Nagaraja, D; Christopher, Rita

doi:10.1016/j.clnu.2017.07.005

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…It has been reported that in patients affected by homocysteinuria, total homocysteine levels can easily raise up to 400-500 μM. However, in plasma of patients, about 70% of total Hcy is bound to protein cysteine residues via disulfidebond, and only 30% is in a free form [42,43]. Moreover, the "soluble fraction" of homocysteine includes homocystine, and different types of mixed disulfides including homocysteine-cysteine, and homocysteineglutathione, while the reduced free form of homocysteine does not exceed 2% of total homocysteine content [44].…”

Section: Discussionmentioning

confidence: 99%

S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset

Leri

Rebuzzini

Caselli

et al. 2020

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background: L-Homocysteine (Hcy) is a non-proteinogenic α-amino acid synthesized from dietary methionine. In healthy humans, high Hcy levels are a risk factor for cardiovascular diseases, stroke and type 2 diabetes. A recent study reports that Hcy reacts with Cys 10 of transthyretin (TTR), generating a stable covalent adduct. However, to date the effect of S-homocysteinylation on TTR conformational stability remains unknown. Methods: The effect of Hcy on the conformational properties of wt-and L55P-TTR were analysed using a set of biophysical techniques. The cytotoxicity of S-homocysteinylated L55P-TTR was also evaluated in the HL-1 cardiomyocyte cell line, while the effects of the assemblies on kinematic and dynamics properties of cardiac muscle cells were analysed in cardiomyocyte syncytia. Results: We found that Hcy stabilizes tetrameric wt-TTR, while it destabilizes the tetrameric structure of the L55P mutant, promoting the accumulation of self-assembly-prone monomeric species. Conclusions: Our study demonstrated that S-homocysteinylation of the L55P-TTR mutant impairs protein stability, favouring the appearance of toxic monomers. Interestingly, S-homocysteinylation affected only mutant, not wt-TTR. Moreover, we also show that assemblies of S-homocysteinylated L55P-TTR impair cardiomyocytes functional parameters. General significance: Our study offers new insights on the negative impact of S-homocysteinylation on L55P-TTR stability, whose aggregation is considered the causative agent of a form of early-onset familial amyloid polyneuropathy and cardiomyopathy. Our results suggest that high homocysteine levels are a further risk factor for TTR cardiomyopathy in patients harbouring the L55P-TTR mutation.

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Section: Discussionmentioning

confidence: 99%

S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset

Leri

Rebuzzini

Caselli

et al. 2020

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…Human CVD represents the leading causes of death globally, and therapy of human CVD has always remains one of the biggest challenges in clinic. High levels of plasma Hcy as an independent risk factor contributes to the occurrence and development of CVD (Feng and Xu, 2017 ; Markišić et al, 2017 ; Rudreshkumar et al, 2017 ). Accumulated studies have indicated that Hcy as an intermediate metabolite of cysteine and methionine can cause endothelial dysfunction (Zhang et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage

Fan

Sun

et al. 2017

Front. Physiol.

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Homocysteine (Hcy) as an independent risk factor contributes to the occurrence and development of human cardiovascular diseases (CVD). Induction of oxidative stress and apoptosis was commonly accepted as the major mechanism in Hcy-induced cardiotoxicity. Astaxanthin (ATX) as one of the most powerful antioxidants exhibits novel cardioprotective potential against Hcy-induced endothelial dysfunction. However, the protective effect and mechanism of ATX against Hcy-induced cardiotoxicity in cardiomyocytes have not been elucidated yet. Herein, H9c2 rat cardiomyocytes and Hcy-injured animal model were employed in the present study. The MTT, flow cytometry analysis (FCM), TUNEL-DAPI and western blotting results all demonstrated that ATX significantly alleviated Hcy-induced cytotoxicity in H9c2 cells through inhibition of mitochondria-mediated apoptosis. The JC-1 and Mito-tracker staining both revealed that ATX pre-treatment blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family expression. Moreover, DCFH-DA and Mito-SOX staining showed that ATX effectively attenuated Hcy-induced oxidative damage via scavenging intracellular reactive oxygen species (ROS). Importantly, the ELISA and immunohistochemical results indicated that Hcy-induced cardiotoxicity in vivo was also significantly inhibited by ATX through inhibition of oxidative damage and apoptosis, and improvement of the angiogenesis. Taken together, our results demonstrated that ATX suppressed Hcy-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Our findings validated the strategy of using ATX may be a highly efficient way to combat Hcy-mediated human CVD.

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“…Homocysteine (Hcy) has been involved in the pathogenesis of hypertension by producing endothelial injury [3,4], increasing oxidative stress [5], stimulating the proliferation of vascular smooth muscle cells (VSMCs) [6], and altering the elastic properties of the vascular wall [7]. Elevated Hcy and its related genetic variants have been associated with blood pressure [8][9][10][11][12], hypertension [13][14][15], and related vascular complications, e.g., atherosclerosis [16,17], coronary heart disease [18,19], and stroke [20,21], in humans. In the process of Hcy-induced hypertension, the endothelial injury resulting from Hcy promotes platelet consumption and adherence which stimulates the proliferation of VSMCs through releasing mitogenic factors [22], thereby contributing to atherosclerosis, arterial stiffness, and high blood pressure [23,24] Furthermore, platelet activation has been associated with Hcy [25] but also hypertension [26] in population studies.…”

Section: Introductionmentioning

confidence: 99%

Modification of Platelet Count on the Association between Homocysteine and Blood Pressure: A Moderation Analysis in Chinese Hypertensive Patients

Zhang

Shi

et al. 2020

International Journal of Hypertension

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Background. Platelet consumption followed by homocysteine-induced endothelial injury suggests a crosstalk between platelet activation and homocysteine on hypertension. Platelet count has been found to modify the effect of folic acid on vascular health. However, whether platelet count could modify the contribution of homocysteine to blood pressure (BP) remains unclear. Methods. Leveraging a community-based cross-sectional survey in 30,369 Chinese hypertensive patients (mean age 62 years, 52% female), we examined the moderation of platelet count on the association between serum homocysteine and BP by constructing hierarchical multiple regression models, adjusting for conventional risk factors. If adding the interaction term of homocysteine and platelet count could explain more variance in BP and the interaction is significant, then we believe that moderation is occurring. Results. e association between serum homocysteine and diastolic BP was significantly stronger (β = 0.092 vs. 0.035, P � 0.004) in participants with low platelet count (<210 × 10 9 /L) than in those with high platelet count (≥210 × 10 9 /L). Adding the interaction term of homocysteine and platelet count additionally explained 0.05% of the variance in diastolic BP (P � 0.0001), and the interaction was significant (β = − 0.021, P < 0.001). Excluding participants receiving antihypertensive medications did not change our results. Conclusions. e association between homocysteine and BP was significantly stronger in participants with low vs. high platelet count and was partially moderated by platelet count. ese results indicate that platelet count may be useful in the identification of individuals who are most beneficial to reducing-homocysteine treatments but this usefullness still needs further investigation.

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Relevance of plasma levels of free homocysteine and methionine as risk predictors for ischemic stroke in the young

Cited by 20 publications

References 34 publications

S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset

S-Homocysteinylation effects on transthyretin: worsening of cardiomyopathy onset

Astaxanthin Attenuates Homocysteine-Induced Cardiotoxicity in Vitro and in Vivo by Inhibiting Mitochondrial Dysfunction and Oxidative Damage

Modification of Platelet Count on the Association between Homocysteine and Blood Pressure: A Moderation Analysis in Chinese Hypertensive Patients

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