Abstract:Background: Carotid artery atherosclerotic stenosis is a preventable major cause of stroke, but there is still a need for definition of high-risk plaque in asymptomatic patients who might benefit from interventional therapies. Several image markers are recommended to characterize unstable plaques. The measurement of serum biomarkers is a promising method to assist in decision making, but the lack of robust evidence in the carotid environment burdens their potential as a standard of care. The goal of this revie… Show more
“…1A). Impaired regulation of the HM cycle results in elevated levels of Hcy, a human disease termed as hyperhomocysteinemia (HHcy), an established independent risk factor for cardiovascular disease (CVD), stroke, type II diabetes, osteoporosis and dementia [[1], [2], [3]]. Fig.…”
Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease.We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-β-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other.We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection.
“…1A). Impaired regulation of the HM cycle results in elevated levels of Hcy, a human disease termed as hyperhomocysteinemia (HHcy), an established independent risk factor for cardiovascular disease (CVD), stroke, type II diabetes, osteoporosis and dementia [[1], [2], [3]]. Fig.…”
Homocysteine-Methionine (HM) cycle produces universal methyl group donor S-adenosylmethione (SAM), methyltransferase inhibitor S-adenosylhomocysteine (SAH) and homocysteine (Hcy). Hyperhomocysteinemia (HHcy) is established as an independent risk factor for cardiovascular disease (CVD) and other degenerative disease.We selected 115 genes in the extended HM cycle (31 metabolic enzymes and 84 methyltransferases), examined their protein subcellular location/partner protein, investigated their mRNA levels and mapped their corresponding histone methylation status in 35 disease conditions via mining a set of public databases and intensive literature research. We have 6 major findings. 1) All HM metabolic enzymes are located only in the cytosol except for cystathionine-β-synthase (CBS), which was identified in both cytosol and nucleus. 2) Eight disease conditions encountered only histone hypomethylation on 8 histone residues (H3R2/K4/R8/K9/K27/K36/K79 and H4R3). Nine disease conditions had only histone hypermethylation on 8 histone residues (H3R2/K4/K9/K27/K36/K79 and H4R3/K20). 3) We classified 9 disease types with differential HM cycle expression pattern. Eleven disease conditions presented most 4 HM cycle pathway suppression. 4) Three disease conditions had all 4 HM cycle pathway suppression and only histone hypomethylation on H3R2/K4/R8/K9/K36 and H4R3. 5) Eleven HM cycle metabolic enzymes interact with 955 proteins. 6) Five paired HM cycle proteins interact with each other.We conclude that HM cycle is a key metabolic sensor system which mediates receptor-independent metabolism-associated danger signal recognition and modulates SAM/SAH-dependent methylation in disease conditions and that hypomethylation on frequently modified histone residues is a key mechanism for metabolic disorders, autoimmune disease and CVD. We propose that HM metabolism takes place in the cytosol, that nuclear methylation equilibration requires a nuclear-cytosol transfer of SAM/SAH/Hcy, and that Hcy clearance is essential for genetic protection.
“…Previous studies focused on inflammatory markers within the atherosclerotic plaque and revealed distinct cytokine signatures associated with plaque vulnerability 13 . Likewise, numerous studies investigated circulating biomarkers regarding presence of carotid stenosis or measures of cerebrovascular risk 14 www.nature.com/scientificreports/ local plaque inflammation 15,16 or rather an atherothrombotic event leading to cerebrovascular symptoms. To answer this question, we chose a comprehensive approach in order to identify a systemic cytokine pattern that is associated with characteristics of vulnerability or with the occurrence of ischaemic cerebrovascular events in carotid artery stenosis.…”
Inflammatory processes are crucial in atherosclerosis and atherothrombosis. This study aimed to identify a cytokine-pattern that is associated with plaque-vulnerability or symptomatic state in comprehensively investigated patients with symptomatic (sCS) and asymptomatic carotid stenosis (aCS). Twenty-two patients with sCS and twenty-four patients with aCS undergoing carotid endarterectomy (CEA) were considered. A cytokine-panel was measured in plasma-specimens prior to surgery and at a 90 day follow-up. Doppler-ultrasound detecting microembolic signals (MES) in the ipsilateral middle cerebral artery was performed. Carotid plaques were analysed regarding histopathological criteria of plaque-vulnerability and presence of chemokine receptor CXCR4. Correction for multiple comparisons and logistic regression analysis adjusting for vascular risk factors, grade of stenosis, antithrombotic and statin pretreatment were applied. In sCS-patients higher plasma-levels of Fractalkine (CX3CL1), IFN-α2, IL-1β, IL-2, IL-3, IL-7 were found compared to aCS-patients. CXCR4-expression on inflammatory cells was more evident in sCS- compared to aCS-plaques and was associated with vulnerability-criteria. In contrast, plasma-cytokine-levels were not related to CXCR4-expression or other vulnerability-criteria or MES. However, in both groups distinct inter-cytokine correlation patterns, which persisted at follow-up and were more pronounced in the sCS-group could be detected. In conclusion, we identified a distinct cytokine/chemokine-network in sCS-patients with elevated and closely correlated mediators of diverse functions.
“…In ammatory factor (eg. IL-6), lipid, MMP-9, adiponectin, neutrophil count and total bilirubin have the potentials to improve the plaque de nition in complications, thereby choosing asymptomatic patients for the interventional therapies [19]. IL-6 is a proin ammatory cytokine that has a role in the development of atherosclerotic plaque, and miR-126 mimic has been found to degrade the secretion of in ammatory cytokines [20].…”
Background
Numerous researches have demonstrated the essential functions of microRNAs (miRNAs) in cardiovascular disease. Herein, we want to probe into the roles of miR-126 and miR-223 in the prediction of plaque stability of carotid atherosclerosis (CA).
Methods
First, miRNA microarray was performed to analyze the differentially expressed miRNA in serum of normal controls and CA patients. Next, the differential expression of miR-223 and miR-126 in CA was verified and the correlations of their expression levels with plaque stability-related factors were analyzed. Then, the predictive efficacy of miR-223 and miR-126 on plaque stability was analyzed by receiver operating characteristic curve, then the targeting relationships of miR-223 and miR-126 with COX2 were verified by online prediction and luciferase activity assay. Finally, the relationship between COX2 expression and CA plaque stability was analyzed.
Results
Expression levels of miR-223 and miR-126 were decreased in the serum of CA patients and they had good diagnostic efficacy for CA. Additionally, we found that the expression levels of miR-223 and miR-126 in the serum of CA patients with unstable plaque were lower than those with stable plaque. miR-223 and miR-126 were negatively correlated with plaque instability-related indicators, while COX2, a direct target gene of miR-223 and miR-126, was positively related to plaque instability-related indicators.
Conclusion
This study indicates that miR-223 and miR-126 are lowly expressed in serum of CA patients, which can be used as a clinical indicator for predicting the plaque stability in CA patients.
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