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Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review.

ABSTRACT: Somatic DNA alterations are known to occur in atherosclerotic carotid artery lesions; however, their significance is unknown. The accumulation of microsatellite mutations in coding DNA regions may reflect a deficiency of the DNA mismatch repair (MMR) system. Alternatively, accumulation of these coding microsatellite mutations may indicate that they contribute to the pathology. To discriminate between these two possibilities, we compared the mutation frequencies in coding microsatellites (likely functionally relevant) with those in noncoding microsatellites (likely neutral). Genomic DNA was isolated from carotid endarterectomy (CEA) specimens of 26 patients undergoing carotid surgery and from 15 nonatherosclerotic control arteries. Samples were analyzed by DNA fragment analysis for instability at three noncoding (BAT25, BAT26, CAT25) and five coding (AIM2, ACVR2, BAX, CASP5, TGFBR2) microsatellite loci, with proven validity for detection of microsatellite instability in neoplasms. We found an increased frequency of coding microsatellite mutations in CEA specimens compared with control specimens (34.6 versus 0%; p = 0.0013). Five CEA specimens exhibited more than one frameshift mutation, and ACVR2 and CASP5 were affected most frequently (5/26 and 6/26). Moreover, the rate of coding microsatellite alterations (15/130) differed significantly from that of noncoding alterations (0/78) in CEA specimens (p = 0.0013). In control arteries, no microsatellite alterations were observed, neither in coding nor in noncoding microsatellite loci. In conclusion, the specific accumulation of coding mutations suggests that these mutations play a role in the pathogenesis of atherosclerotic carotid lesions, since the absence of mutations in noncoding microsatellites argues against general microsatellite instability, reflecting MMR deficiency.

SUBMITTER: Kurz C

PROVIDER: S-EPMC4607617 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review.

Kurz Carolin C Hakimi Maani M Kloor Matthias M Grond-Ginsbach Caspar C Gross-Weissmann Marie-Luise ML Böckler Dittmar D von Knebel Doeberitz Magnus M Dihlmann Susanne S

Molecular medicine (Cambridge, Mass.) 20150609

Somatic DNA alterations are known to occur in atherosclerotic carotid artery lesions; however, their significance is unknown. The accumulation of microsatellite mutations in coding DNA regions may reflect a deficiency of the DNA mismatch repair (MMR) system. Alternatively, accumulation of these coding microsatellite mutations may indicate that they contribute to the pathology. To discriminate between these two possibilities, we compared the mutation frequencies in coding microsatellites (likely ...[more]

PMID: 26070012

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Project description:BACKGROUND:The presence of intraplaque haemorrhage (IPH) has been related to plaque rupture, is associated with plaque progression, and predicts cerebrovascular events. However, the mechanisms leading to IPH are not fully understood. The dominant view is that IPH is caused by leakage of erythrocytes from immature microvessels. The aim of the present study was to investigate whether there is an association between atherosclerotic plaque microvasculature and presence of IPH in a relatively large prospective cohort study of patients with symptomatic carotid plaque. METHODS:One hundred and thirty-two symptomatic patients with ?2?mm carotid plaque underwent cardiovascular magnetic resonance (CMR) of the symptomatic carotid plaque for detection of IPH and dynamic contrast-enhanced (DCE)-CMR for assessment of plaque microvasculature. Ktrans, an indicator of microvascular flow, density and leakiness, was estimated using pharmacokinetic modelling in the vessel wall and adventitia. Statistical analysis was performed using an independent samples T-test and binary logistic regression, correcting for clinical risk factors. RESULTS:A decreased vessel wall Ktrans was found for IPH positive patients (0.051?±?0.011?min-?1 versus 0.058?±?0.017?min-?1, p?=?0.001). No significant difference in adventitial Ktrans was found in patients with and without IPH (0.057?±?0.012?min-?1 and 0.057?±?0.018?min-?1, respectively). Histological analysis in a subgroup of patients that underwent carotid endarterectomy demonstrated no significant difference in relative microvessel density between plaques without IPH (n?=?8) and plaques with IPH (n?=?15) (0.000333?±?0.0000707 vs. and 0.000289?±?0.0000439, p?=?0.585). CONCLUSIONS:A reduced vessel wall Ktrans is found in the presence of IPH. Thus, we did not find a positive association between plaque microvasculature and IPH several weeks after a cerebrovascular event. Not only leaky plaque microvessels, but additional factors may contribute to IPH development. TRIAL REGISTRATION:NCT01208025 . Registration date September 23, 2010. Retrospectively registered (first inclusion September 21, 2010). NCT01709045 , date of registration October 17, 2012. Retrospectively registered (first inclusion August 23, 2011).

Project description:BackgroundThis study explored the serum concentrations of miR-26 in patients with carotid atherosclerosis (CAS) and defined the roles and mechanisms of miR-26 derived from the exosomes of adipose-derived stem cells (ADSC-exos).MethodsThe carotid artery width was diagnosed by ultrasound examination in patients with different degrees of CAS. The serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in patients were detected by biochemistry. The serum levels of miR-26 were determined by quantitative polymerase chain reaction (qPCR). A model of CAS in ApoE-/- mice fed with a rich-fat diet was established to analyze the regulatory effects of serum miR-26 on blood lipids in mice. Adipose mesenchymal stem cell lines transfected with miR-26 were established. The regulatory relationship between the expression levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β, and the expression levels of miR-26 in the supernatant of each group of cells was determined by qPCR. The ADSC-exos were extracted from ADSCs and injected into model mice through the tail vein. The therapeutic effect of ADSCs expressing miR-26 on model mice was evaluated by detecting the levels of inflammatory factors and blood lipids in the serum of the mice.ResultsThe degree of atherosclerosis (AS) was positively associated with the intima-media thickness (IMT) of the carotid artery. The serum levels of miR-26 in patients were inversely correlated with the levels of blood lipids (TC, TG, and LDL-C), and positively correlated with HDL-C levels. Similarly, in the CAS mouse model, the serum levels of miR-26 were inversely correlated with the levels of blood lipids (TC, TG, and LDL-C), and positively correlated with HDL-C level. In ADSCs transfected with miR-26, the miR-26 expression in the cell supernatant was negatively regulated by the expression of inflammatory factors, TNF-α, IL-6, and IL-1β, in the cell supernatant. ADSC-exos expressing miR-26 has positive effects on correcting blood lipids and inflammatory factors in the mouse model of CAS.ConclusionsmiR-26 has an active role in CAS and may be a novel target for the treatment of CAS in the future.

Dataset Information

Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review.

Publications

Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review.

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