ABSTRACT
OBJECTIVE: To compare the circulating levels of MMP-2 and TIMP-2 and the MMP-2/TIMP-2 ratio in control, obese, and obese hypertensive children and adolescents and to assess whether hypoadiponectinemia is associated with MMP-2 and TIMP-2 levels and MMP-2/TIMP-2 ratios. METHODS: Studies were carried out with 53 control, 73 obese, and 29 obese hypertensive children and adolescents in this cross-sectional study. Adiponectin and TIMP-2 concentrations were measured by ELISA. MMP-2 concentrations were measured by gelatin zymography. Multiple linear regression analysis was carried out to assess the effects of adiponectin on MMP-2 and TIMP-2 levels and MMP-2/TIMP-2 ratios. RESULTS: The obese hypertensive group had the lowest adiponectin levels among groups (P < 0.05) while obese subjects had lower adiponectin levels than control subjects (P < 0.05). Obese hypertensive subjects also had higher circulating MMP-2 concentrations than obese subjects (P < 0.05) and had the highest MMP-2/TIMP-2 ratios among groups (P < 0.05). Moreover, obese/hypertensive subjects had the lowest TIMP-2 levels among groups (P < 0.05). A multiple linear regression analysis showed that MMP-2 levels and MMP-2/TIMP-2 ratios are negatively associated with adiponectin levels (P = 0.034 and P = 0.011, respectively) while TIMP-2 levels is positively associated with adiponectin levels (P = 0.013). CONCLUSIONS: Increased activity of MMP-2 (MMP-2/TIMP-2 ratio) and reduced TIMP-2 levels may play an important role in clinical hypertension of childhood obesity. Additionally, hypoadiponectinemia may contribute to increased activity of MMP-2 in obese/hypertensive children and adolescents.
Subject(s)
Adiponectin/deficiency , Hypertension/metabolism , Matrix Metalloproteinase 2/metabolism , Metabolism, Inborn Errors/metabolism , Pediatric Obesity/metabolism , Adiponectin/metabolism , Adolescent , Case-Control Studies , Child , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Hypertension/complications , Male , Matrix Metalloproteinase 2/blood , Metabolism, Inborn Errors/complications , Pediatric Obesity/complications , Regression Analysis , Tissue Inhibitor of Metalloproteinase-2/bloodABSTRACT
Matrix metalloproteinase-2 is involved in the development of the adipose tissue, and associated with cardiovascular diseases. Metabolic risk factors (MRFs) and functional polymorphisms in the MMP-2 gene may affect its expression and activity. We investigated whether traditional MRFs and two MMP-2 gene polymorphisms (C(-1306)T; rs243865, and C(-735)T; rs2285053) affect circulating MMP-2 levels in children and adolescents, and whether MMP-2 polymorphisms and/or haplotype are associated with susceptibility to childhood obesity. We studied 114 healthy controls, 43 obese, and 83 obese with ≥ 3 MRFs children and adolescents. Genotypes were determined by Taqman allele discrimination assay and real-time PCR. Plasma MMP-2 was measured using zymography. We found positive correlations between MMP-2 concentrations and mean blood pressure in all children and adolescents group (r = 0.132; P < 0.05) and in obese children and adolescents (r = 0.247; P < 0.01). We found that the CC genotype for the C(-1306)T polymorphism was more common in subjects with higher MMP-2 concentrations in controls (P = 0.003) and in the obese group (P = 0.013). The CT genotype (OR = 0.40; P < 0.01) and the T allele (OR = 0.48; P < 0.01) for the C(-735)T polymorphism were less common in obese children and adolescents than in controls. The haplotypes distribution did not show significant differences between control and obese (P > 0.05). Ours findings show that blood pressure is associated with circulating MMP-2 concentrations, and that the CC genotype for the C(-1306)T polymorphism was more common subjects (controls and obese) with higher MMP-2 concentrations, whereas the CT genotype and the T allele for the C(-735)T polymorphism are less common in obesity.
Subject(s)
Matrix Metalloproteinase 2/blood , Matrix Metalloproteinase 2/genetics , Metabolic Syndrome/complications , Pediatric Obesity/etiology , Adolescent , Alleles , Case-Control Studies , Child , Female , Gene Frequency , Genotype , Haplotypes , Humans , Male , Pediatric Obesity/blood , Pediatric Obesity/genetics , Risk FactorsABSTRACT
We investigated whether genetic polymorphisms in the endothelial nitric oxide (eNOS) gene (T(786)C in the promoter region, Glu298Asp in exon 7, and 4b/4a in intron 4) or eNOS haplotypes are associated with metabolic syndrome (MetS) in obese children and adolescents. We studied 242 subjects: 108 healthy (controls), 64 normotensive obese, and 70 obese children and adolescents with MetS. Genotypes were determined by Taqman(®) allele discrimination assay and real-time polymerase chain reaction (PCR), and PCR followed by fragment separation by electrophoresis. We compared the distribution of eNOS genotypes, alleles, and haplotypes in the three groups of subjects. The CC genotype for the T(786)C polymorphism was more common in the MetS group than in the control group (OR = 3.27; CI 1.81-9.07; P < 0.05). However, we found no significant differences in the distribution of eNOS haplotypes (P > 0.00625; P for significance after correction for multiple comparisons). Our findings suggest that while eNOS haplotypes are not relevant, the CC genotype for the T(786)C polymorphism is associated with MetS in obese children and adolescents. Further studies examining interactions of eNOS haplotypes with environmental factors and other genetic markers are warranted.
Subject(s)
Metabolic Syndrome/genetics , Minisatellite Repeats , Nitric Oxide Synthase Type III/genetics , Polymorphism, Single Nucleotide , Adolescent , Child , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Metabolic Syndrome/enzymology , Obesity/enzymology , Obesity/genetics , Promoter Regions, Genetic , Sequence Analysis, DNAABSTRACT
O hipercortisolismo crônico é a causa mais freqüente de osteoporose secundária, acometendo principalmente o osso trabecular. Aproximadamente 30-35 por cento dos pacientes com síndrome de Cushing apresentam fraturas de vértebras por compressão e o risco de fraturas de colo de fêmur é aumentado em 50 por cento nessa população. Vários mecanismos têm sido propostos para explicar a ocorrência de osteoporose nessa condição, como a ação direta dos glicocorticóides nas paratireóides e nas células ósseas, alterações na produção de prostaglandinas, citocinas, interleucinas, alterações na secreção do hormônio do crescimento (GH), do fator insulina símile-I (IGF-I) e esteróides gonadais. Resultados controversos têm sido apresentados quanto à alteração na secreção do PTH nesta situação, onde níveis normais e elevados têm sido descritos. A elevação da secreção de PTH pode ser secundária a distúrbios do metabolismo mineral induzidos pelo hipercortisolismo, como diminuição na absorção intestinal, aumento da excreção renal de cálcio, diminuição no número de receptores paratireoideanos para a 1,25(OH)2D3, anormalidades no limiar de sensibilidade do cálcio (set point) para a secreção do PTH e alteração na sua atividade. Nesta revisão, são discutidos diversos aspectos fisiopatológicos e possíveis mecanismos envolvidos na associação entre hipercortisolismo e osteoporose.
