Elsevier

Metabolism

Volume 56, Issue 6, June 2007, Pages 799-805
Metabolism

Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese children and adolescents

https://doi.org/10.1016/j.metabol.2007.01.011Get rights and content

Abstract

Matrix metalloproteinases (MMPs) have been implicated in the atherosclerotic process and risk factors for the disease such as hypertension, hyperlipidemia, or diabetes mellitus in adults. So far, circulating levels of MMPs and their tissue inhibitors (TIMPs) have not been assessed in children and adolescents with obesity, a known risk factor for cardiovascular disease. Plasma levels of MMP-9 and TIMP-1 were measured immunoenzymatically in 45 obese children and adolescents, aged 15 ± 1.8 years. The control group consisted of 28 healthy children, aged 14.5 ± 2.5 years. MMP-9 and TIMP-1 concentrations were higher in obese children than in the control group (MMP-9: 553.5 ± 311 vs 400.4 ± 204 ng/mL, respectively; P = .02; TIMP-1: 161.2 ± 32 vs 143.1 ± 20.1 ng/mL, respectively; P = .03). We found significantly higher levels of MMP-9 in obese children with coexisting hypertension than in obese normotensive patients (635 ± 308 vs 450 ± 289 ng/mL, respectively; P = .04). MMP-9 correlated with body mass index (BMI) (r = 0.33, P = .005) and fasting insulin (r = 0.3, P = .013); TIMP-1 correlated with BMI (r = 0.35, P = .006). In the group of obese hypertensive children (n = 25), MMP-9 correlated with BMI (r = 0.41, P = .001), systolic blood pressure (r = 0.41, P = .002), fasting insulin (r = 0.37, P = .006), and homeostasis model assessment index of insulin resistance (r = 0.27, P = .03). TIMP-1 correlated with BMI (r = 0.33, P = .025) and systolic (r = 0.38, P = .008) and diastolic (r = 0.47, P = .001) blood pressure. In the regression models, MMP-9 was found to be dependent on fasting insulin (R2 = 0.16, P = .04), and TIMP-1 on BMI (R2 = 0.14, P = .04). In the obese hypertensive group, TIMP-1 was dependent on diastolic blood pressure (R2 = 0.18, P = .04). Obese children and adolescents have elevated plasma concentrations of MMP-9 and TIMP-1. Coexistence of hypertension may exacerbate alterations of extracellular matrix turnover in these patients. It might be hypothesized that elevated MMP and TIMP concentrations may be related to increased cardiovascular risk in obese and particularly in obese hypertensive children and adolescents.

Introduction

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases capable of degrading components of the extracellular matrix (ECM) and basement membranes. This ability to modify the structural integrity is essential in physiologic tissue remodeling. However, the dysregulation or activation of MMP expression is associated with numerous pathologic conditions associated with an unbalanced turnover of the ECM such as arthritis, wound healing, and tumor growth [1], [2]. Lately, MMPs and their inhibitors (tissue inhibitors of metalloproteinases [TIMPs]) have been implicated in various cardiovascular diseases (CVD) that include acute coronary events, restenosis, dilated cardiomyopathy, heart failure, and myocardial infarction [2], [3], [4]. A large body of evidence asserts the importance of MMPs in atherosclerosis [1].

Atherosclerosis is a chronic inflammatory disease involving, among others, production and degradation of the ECM and the accumulation of lipids in the arterial wall. MMPs may play a central role in subendothelial vascular ECM remodeling. MMP degradation of the ECM may facilitate infiltration of leukocytes through the endothelial layer, contribute to a decrease in endothelial barrier function with increased influx of plasma lipoproteins, and facilitate migration of vascular smooth muscle cells through the internal elastic lamina into the intimal space where they proliferate and contribute to plaque formation [5], [6], [7], [8].

Cardiovascular disease constitutes the leading cause of morbidity and mortality worldwide [9]. Atherosclerosis is the main underlying pathophysiologic process involved, although it remains not fully understood. MMPs and TIMPs may constitute an additional group of biomarkers in the inflammatory atherosclerotic process. Alterations in MMP expression in the arterial intima can be detected by determination of their systemic concentration. Some studies have revealed elevation in circulating levels of MMPs not only after acute coronary syndromes, but also in patients with early atherosclerosis and risk factors for the disease [10], [11]. Atherosclerosis begins early in life and gradually progresses through adolescence and youth. The process is accelerated in children in whom risk factors for the disease are present. Autopsy studies have shown that the presence of fatty streaks and more advanced changes in the aorta and coronary arteries of children and young adults was related to body mass index (BMI) [12], [13].

Obesity in childhood is becoming a significant health issue in developed as well as in developing countries [14], [15]. Childhood obesity increases the risk of atherosclerosis and premature all-cause mortality later in life [16]. Already in the young, it is correlated with the constellation of other atherosclerosis risk factors such as hypertension, hyperlipidemia, and insulin resistance [17]. In our previous studies we found elevated levels of adhesion molecules (sICAM-1, sVCAM-1) and sE-selectin in obese children and adolescents, concluding that endothelial activation appears in these children and adhesion molecules are related to the earliest stages of atherosclerosis [18].

No information is available so far on the levels of MMPs in childhood obesity and their possible role in the process of atherosclerosis in the young. We chose to measure plasma MMP-9 and TIMP-1 because clinical data support an important role of these 2 enzymes in cardiovascular pathology and identified them as novel predictors of cardiovascular risk [19], [20], [21], [22]. The aim of this study was to investigate the levels of MMP-9 and TIMP-1 in obese children and adolescents and to estimate the MMP-9 and TIMP-1 levels in disturbances connected with childhood obesity, such as hypertension, insulin resistance, hyperlipidemia, and positive family history of CVDs.

Section snippets

Subjects

The study population consisted of 45 obese children and adolescents (22 boys and 26 girls, aged 15 ± 1.8 years) recruited from patients of the 2nd Department of Children's Diseases of the Medical University of Biaƚystok, Poland, and its related outpatient clinic for endocrinology. Obese children were divided and then compared according to accompanying alterations into groups: (1) hypertensive (n = 25) vs normotensive, (2) hyperlipidemic (n = 16) vs normolipidemic, (3) insulin resistant (n = 11)

Results

The clinical characteristics of the study groups are presented in Table 1. The obese group had higher body mass and BMI, as expected. Lipid levels, blood pressure values, fasting insulin, and HOMA IR were also found to be significantly different from that of the control group (Table 1).

MMP-9 concentration was significantly higher in obese children than in the control group (553.5 ± 311 vs 400.4 ± 204 ng/mL, respectively; P = .02). TIMP-1 concentration was also higher in the study group than in

Discussion

The main finding of this study is that obese children and adolescents, a group at increased risk of CVD, have elevated circulating levels of MMP-9 and TIMP-1. Both MMP-9 and TIMP-1 correlated positively with BMI. Data on the levels of MMPs and TIMPs in obesity in humans appear to be lacking. To our knowledge there are no data in such a young population so far.

In morbidly obese adult women (BMI, 42.5 kg/m2) undergoing gastric banding and 1-year postsurgical treatment, a positive correlation

Limitations

Our study has, however, certain limitations, so that conclusions should be drawn very carefully. Peripheral blood measurements of MMPs and/or TIMPs are limited by the lack of standardized analytical procedures, including the nature of tested samples (serum, heparinized plasma), the nature of the measured MMP molecule (total MMP, pro MMP), and the detection limit of commercially available assays. Ideally, correlations should be established between tissue activity and circulating MMP-9 and TIMP-1

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