-
[show abstract]
[hide abstract]
ABSTRACT: Interleukin (IL)-beta plays a central role in inflammation and atherosclerosis, but levels of IL-1beta, its natural antagonist, IL-1Ra, and their balance in human atherosclerotic lesions, are unknown. Knowledge of protein levels in atherosclerosis and the influence of a functional IL-1Ra polymorphism would increase the understanding of atherosclerosis pathogenesis.
Fresh and endotoxin-stimulated explanted human atherosclerotic and normal arteries were analyzed for IL-1beta, IL-1Ra and IL-1 receptor 1 (IL-1R1) using TaqMan PCR and enzyme-linked immunosorbent assay. Two hundred forty-three survivors of a first myocardial infarction were genotyped for a polymorphism in IL-1Ra and their coronary atherosclerosis analyzed by using coronary angiography. Levels of IL-1beta, IL-1Ra and IL-1R1 mRNA were significantly increased in atherosclerotic arteries compared with normal arteries. Endotoxin stimulation increased IL-1beta levels more than IL-1Ra levels (ie, promoted a pro-inflammatory state). A polymorphism in IL-1Ra known to increase levels of IL-1Ra was associated with decreased mean coronary artery plaque area.
Activation of innate immunity changed the balance between IL-1beta and IL-1Ra in atherosclerotic arteries towards a more pro-inflammatory state. In line with this, the presence of an IL-1Ra intron 2 polymorphism known to increase IL-1Ra levels, and possibly the IL-1Ra:IL-1beta ratio, was associated with reduced coronary atherosclerosis.
Circulation Journal 08/2009; 73(8):1531-6. · 3.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation, which correlate with increased mortality.
To determine the molecular mechanisms mediating decreased capillary formation in COPD.
24 patients with COPD and 12 matching controls were recruited. Patients with COPD were classified into mild, moderate and severe groups according to GOLD (global initiative for chronic obstructive lung disease) criteria. Biopsy specimens were obtained from the tibialis anterior muscle. Fibre typing and capillary formation, together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF1alpha and HIF3alpha), vascular endothelial growth factors (VEGF-A, VEGF-B and VEGF-C isoforms) and von Hippel-Lindau (VHL) protein, were determined. VHL expression and localisation were further studied by immunohistochemistry.
Skeletal muscle capillary formation decreased significantly with increasing disease severity. Compared with controls, a tendency to mRNA overexpression of HIF1alpha, HIF3alpha and VEGF isoforms was observed in mild and moderate COPD, which decreased at the severe stage. In contrast, skeletal muscle biopsy samples from patients with COPD exhibited significant overexpression of VHL at both the mRNA and protein level by immunohistochemistry. VHL protein was further determined to be localised to satellite cells.
Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may have a negative effect on transduction of the hypoxic signal and may contribute to decreased capillarisation in skeletal muscles of patients with COPD.
Journal of clinical pathology 10/2008; 62(1):70-6. · 2.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Eotaxin (CCL11) is a CC chemokine, whose systemic levels might be associated with coronary artery disease (CAD) and genetic variants predispose to the myocardial infarction (MI). However, the relationship between eotaxin genetic variants and plasma concentrations in CAD patients is still incompletely characterized. We genotyped 311 patients, who survived first MI and 338 controls for a 67G>A single nucleotide polymorphism in the eotaxin gene. By measuring plasma eotaxin concentrations in those subjects we related the former to the presence of 67G>A SNP. There were no differences in eotaxin genotype frequencies between patients and controls. Patient G/G carriers had higher circulating eotaxin levels compared both to G/A and A/A patients (P=0.046) and G/G controls (P=0.028), which might indicate the influence of additional factors (e.g. inflammatory mediators) on eotaxin secretion in those patients. At the same time, eotaxin levels did not differ between patients and controls irrespective of the 67G>A SNP variants they carried. There were no associations between plasma eotaxin levels, biochemical indicators of CAD and the degree of coronary artery stenosis in post-MI patients. Interestingly, some medications taken by the patients (e.g. diuretics and short-acting nitrates) might affect plasma eotaxin levels. In conclusion, our results show that there is no clear association between the presence of eotaxin 67G>A SNP, its plasma levels and CAD parameters in post-MI patients and that circulating eotaxin levels do not differ between subjects with clinical manifestations of coronary atherosclerosis and healthy controls.
Atherosclerosis 01/2007; 189(2):458-63. · 3.79 Impact Factor
-
Mehran Ghaderi,
Giovanni Gambelunghe,
Cristina Tortoioli,
Annalisa Brozzetti, Ken Jatta,
Baback Gharizadeh,
Annamaria De Bellis,
Francesca Pecori Giraldi,
Massimo Terzolo,
Corrado Betterle,
Alberto Falorni
[show abstract]
[hide abstract]
ABSTRACT: The polymorphism of class II HLA genes modulates the genetic risk for several endocrine autoimmune diseases. The constitutive class II expression on antigen-presenting cells is under the control of the MHC class II transactivator, encoded by the MHC2TA gene, which is mapped to chromosome 16p13. The MHC2TA -168 A-->G single nucleotide polymorphism (rs3087456) has been suggested to confer susceptibility to some autoimmune diseases.
With the aim of testing whether this MHC2TA single nucleotide polymorphism is independently associated with autoimmune Addison's disease (AAD) and/or modulates the genetic risk conferred by DRB1-DQA1-DQB1 haplotypes, we analyzed DNA samples from 128 AAD patients and 406 healthy control subjects from continental Italy.
Frequency of allele G of MHC2TA was significantly increased among AAD patients (39% alleles), compared with 29% in healthy controls (P = 0.003). Similarly, the frequency of AG+GG genotypes was significantly higher among AAD patients than among healthy control subjects, in both a codominant (P = 0.012) and a G-dominant model (P = 0.018). Multivariate logistic regression analysis showed that MHC2TA AG+GG continued to be positively associated with genetic risk for AAD (P = 0.028, odds ratio = 1.72, 95% confidence interval = 1.06-2.78), after correction for DRB1*03-DQA1*0501-DQB1*0201, DRB1*04 (not 0403)-DQA1*0301-DQB1*0302 and DRB1*0403. Similar results were obtained when the number of G alleles was included in the model (P = 0.004; odds ratio = 1.65, 95% confidence interval = 1.17-2.32).
Our study provides the first demonstration of the association of the polymorphism of the MHC2TA gene with genetic risk for AAD that appears to be independent from the well-known association with the polymorphism of HLA class II genes.
Journal of Clinical Endocrinology & Metabolism 10/2006; 91(10):4107-11. · 6.50 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The proinflammatory cytokine interleukin (IL)-1beta and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1beta levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1beta protein. atRA-treated carotid lesions showed significantly elevated IL-1beta mRNA levels (2.9 +/- 2.33) compared with untreated lesions (2.0 +/- 1.77; p < 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.
Journal of Vascular Research 02/2006; 43(4):377-82. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The release of cytokines and chemokines from activated immune-competent cells plays a crucial role in determining the pathology of the atherogenic progress. We investigated the effect of bacterial lipopolysaccharide (LPS) on cytokine/chemokine expression in carotid lesions and normal renal arteries. The lesions or renal arteries were incubated for 6 h at 37 degrees C in serum-free media treated with or without LPS. After LPS treatment, increased protein levels of IL-1beta, IL-6, IL-8, IL-10, TNF-alpha and MCP-1 were observed in the culture medium from the lesions measured with cytometric bead array. We were able to detect the induction of IL-1beta, IL-6, IL-8, IL-10, TNF-alpha and MCP-1 mRNA in the lesions after stimulation with LPS using real-time PCR. In renal arteries, LPS also induces mRNA expression of all chemokines and cytokines investigated with the exception of IL-6. However, LPS induces significantly higher levels of TNF-alpha, IL-1beta and IL-10 mRNA in lesions compared to renal arteries. The results suggest that infectious agents are capable of enhancing the production of cytokines/chemokines in an already ongoing inflammatory process such as in atherosclerosis, and that low levels of circulating LPS may affect the levels of pro-inflammatory cytokines much more in atherosclerotic vessels than in normal vessels and may contribute to the development of the atherosclerotic lesion.
Journal of Vascular Research 42(3):266-71. · 2.65 Impact Factor
