metallothionein and Carotid-Stenosis

CD14 receptor is a mediator of the inflammatory response to bacterial products. A functional polymorphism in the promoter of the CD14 gene (CD14 C-260T) was associated with coronary heart disease and atherosclerosis albeit with conflicting data.. To better clarify the role of CD14 in atherosclerosis, we typed CD14 C-260T polymorphism in old Italian (Central of Italy) atherosclerotic patients with carotid stenosis related to lipid assessment, inflammation (soluble CD14, IL-6 serum levels) and IL-6, TNF-alpha, IL-10, Metallothioneins (MT) gene expressions in carotid plaques.. There was an increased frequency of TT homozygotes in patients when compared to controls [26% vs. 13.5%, odds ratio=2.25 (95% C.I., 1.23-4.09, p=0.0082) (Fisher's Exact test)]. Subjects with TT genotype showed a significant increase of soluble CD14 and enhanced MT2A, IL-6, TNF-alpha and decreased IL-10 gene expressions within the carotid plaques. On the basis of lipid assessment, hypercholesterolemic -260TT CD14 patients displayed lower HDL cholesterol and higher triglyceride than did CT and CC carriers. Using Pearson's correlation, a high MT2A expression was associated with high IL-6, TNF-alpha, sCD14 and thereby with severe chronic inflammation.. These data provide insight into the pathogenetic role of the CD14 C-260T polymorphism in atherosclerosis as -260TT genotype may favour increased inflammation in atheroma promoting possible worsening atherosclerosis, at least in Central of Italy elderly population. Further studies are in progress in cohorts from different European geographic area (Zincage project).

Topics: Aged; Aged, 80 and over; Atherosclerosis; Carotid Stenosis; Case-Control Studies; Cholesterol; Cytokines; Female; Humans; Italy; Lipopolysaccharide Receptors; Male; Metallothionein; Polymorphism, Genetic; RNA, Messenger

Metallothioneins (MTs) are antioxidant proteins expressed in response to injury. We evaluated MT immunoreactivity in carotid plaques obtained from asymptomatic and symptomatic patients. We also assessed the relationship between ultrasonic plaque echodensity, histological grading, computed tomography findings and MT expression.. In this ongoing prospective study, patients (n = 123, mean age (+/-SD) 68.4 +/- 7.7 years, 97 men) with high-grade carotid stenosis underwent carotid endarterectomy. Specimens were assessed histologically and immunohistochemically. Echolucent plaques (types 1+2) were more common in symptomatic patients (p < 0.0001) and had more advanced histological lesions (p < 0.0001). Echolucent plaques expressed MTs (in macrophages, fibroblasts and T-lymphocytes) significantly more than echogenic plaques (types 3+4) (all p < 0.0001). MT expression was mainly related to carotid plaque echolucency rather than the presence of symptoms. MT expression was significantly more common in advanced histological lesions. Plaques from asymptomatic or symptomatic patients with abnormal computed tomography findings also showed increased MT expression. There was a time-dependent fall in MT expression after cerebrovascular events (p < or = 0.011).. MT overexpression may be triggered in unstable plaques as a local protective factor. There is a need to identify both causative and protective predictors of the 'vulnerable plaque' in the 'vulnerable patient'. Further studies are needed to resolve these issues.

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Carotid Stenosis; Case-Control Studies; Endarterectomy, Carotid; Female; Humans; Immunohistochemistry; Male; Metallothionein; Middle Aged; Observer Variation; Probability; Prognosis; Prospective Studies; Reference Values; Reproducibility of Results; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Sex Factors; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography, Doppler, Duplex

High levels of IL-6 are coupled with impaired immune efficiency, morbidity and mortality in ageing. Elderly men with GG (C-) genotype in -174 locus of IL-6 promoter are disadvantaged for longevity due to higher IL-6 than CG or CC (C+) carriers. As IL-6 increases in atherosclerosis, the study of the polymorphism of IL-6 may be a useful tool in identifying old subjects at risk for atherosclerosis. Thus, we divided old men into C+ and C- genotypes. Natural killer (NK) cell cytotoxicity, IL-6, IL-10, TNF-alpha, MTmRNA and zinc ion bioavailability were also evaluated and compared with nonagenarians and old patients affected by carotid stenosis. Old C- patients display, other than elevated IL-6, higher IL-10, TNF-alpha and MTmRNA coupled with impaired NK cell cytotoxicity and lower zinc ion bioavailability than C+ patients. The same trend is observed in old subjects with C- phenotype. Nonagenarians with C+ genotype show less inflammation, low MTmRNA, satisfactory NK cell cytotoxicity and good zinc bioavailability than long-living individuals with C- genotype. A higher degree of bilateral carotid stenosis is observed in C- patients than in C+ patients (88 vs 52%). Therefore, C- genotype is coupled with chronic inflammation, impaired immune efficiency, low zinc ion bioavailability and high MTmRNA. As such, C- genotype is a risk factor for the appearance of severe atherosclerosis. Thus, the polymorphism of IL-6, together with the analysis of zinc turnover and immune parameters, is of a great clinical relevance in order to genetically identify old subjects at risk in developing severe atherosclerosis and, at the same time, to predict subjects predestined to successful ageing. As a consequence, more convenient therapies may be prepared for a complete recovery.

Topics: Aged; Aged, 80 and over; Aging; Biological Availability; Carotid Artery Diseases; Carotid Stenosis; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-10; Interleukin-6; Killer Cells, Natural; Male; Metallothionein; Middle Aged; Polymorphism, Genetic; RNA, Messenger; Tumor Necrosis Factor-alpha; Zinc