Elevated matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in obese 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
References (44)
- et al.
Soluble adhesion moleclues (sICAM-1, sVCAM-1) and selectins (sE-selectin, sP-selectin, sL-selectin) levels in children and adolescents with obesity, hypertension and diabetes
Metabolism
(2005) - et al.
Plasma levels of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 are increased in the coronary circulation in patients with acute coronary syndrome
Am Heart J
(2001) - et al.
Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation
J Biol Chem
(2003) - et al.
Tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9 levels in patients with hypertension. Relationship to tissue Doppler indices of diastolic relaxation
Am J Hypertens
(2004) - et al.
Matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 levels in essential hypertension. Relationship to left ventricular mass and anti-hypertensive therapy
Int J Cardiol
(2000) - et al.
High glucose alters matrix metalloproteinase expression in two key vascular cells: potential impact on atherosclerosis in diabetes
Atherosclerosis
(2003) - et al.
Effects of age, gender, ethnicity, diurnal variation and exercise on circulating levels of matrix metalloproteinases (MMP)-2 and -9, and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMP)-1 and 2
Thromb Res
(2005) - et al.
Atherosclerosis and proteinase activation
Cardiovasc Res
(2006) - et al.
Matrix metalloproteinases: a review of their structure and role in acute coronary syndrome
Cardiovasc Res
(2003) TIMPs, MMPs and cardiovascular disease
Eur Heart J
(2004)
Vascular remodeling and protease inhibition—bench to bedside
Cardiovasc Res
Inflammation and atherosclerosis
Circulation
Atherosclerosis—an inflammatory disease
N Engl J Med
Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly
Circ Res
Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture
Physiol Rev
The global burden of cardiovascular diseases
Can J Cardiol
Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives
Clin Chem Lab Med
Serum metalloproteinase 9 levels in patients with coronary artery disease: a novel marker of inflammation
J Investig Med
Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults
N Engl J Med
Associations of coronary heart disease risk factors with intermediate lesions of atherosclerosis in youth
Arterioscler Thromb Vasc Biol
Prevalence of overweight and obesity among US children, adolescents and adults 1999-2002
JAMA
Overweight and obesity in preschool children from developing countries
Int J Obes Relat Metab Disord
Cited by (72)
Matrix metalloproteinase −2, −9 and arterial stiffness in children and adolescents: The role of chronic kidney disease, diabetes, and hypertension
2020, International Journal of Cardiology: HypertensionCitation Excerpt :Previous studies assessed the role of different MMPs on arterial structure in CKD and diabetes adult patients and provided inconsistent results [10–14]. However, data on the levels MMPs in pediatric patients and their associations with cardiovascular health are scarce [15,16]. Two previous studies in children with CKD found positive associations of MMP-2 and MMP-9 with biomarkers of stress response (Hsp90-alpha, anti-Hsp60), endothelial dysfunction (sE-selectin), and inflammation (high-sensitivity C-reactive protein) supporting their atherogenic role in childhood CKD [17,18].
Cardiovascular risk biomarkers and metabolically unhealthy status in prepubertal children: Comparison of definitions
2018, Nutrition, Metabolism and Cardiovascular DiseasesCitation Excerpt :Altogether, the increase in PAI-1 and MPO concentrations in MU children with overweight/obesity as early as in the prepubertal stage indicates the importance of these molecules in the increased cardio-metabolic risk in children. Other CVD risk biomarkers such as sE-Selectin, sICAM-1, sVCAM-1 and MMP-9 were increased in children with overweight/obesity but did not differ according to MU status, as previously observed in children [27], adolescents [28] and young adults [29]. The same was observed for pro-inflammatory biomarkers, as the increase of hsCRP, IL-6, and TNF-α concentrations was due to obesity, as previously shown [5,8].
Serum prolidase enzyme activity in obese subjects and its relationship with oxidative stress markers
2017, Clinica Chimica ActaCitation Excerpt :Atherosclerosis, an inflammatory pathology, is characterized with distortion of the ECM and lipid accumulation in the vessel wall. Matrix metalloproteinases might have a pivotal role in the process of inflammatory atherosclerotic cardiovascular diseases [33]. Also, matrix metalloproteinases might have a role in the development of subendothelial vascular ECM remodeling [33].
Evaluation of plasma MMP-8, MMP-9 and TIMP-1 identifies candidate cardiometabolic risk marker in metabolic syndrome: Results from double-blinded nested case-control study
2015, Metabolism: Clinical and ExperimentalProteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications
2015, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Several mechanisms contribute to obesity and/or insulin resistance-induced cardiac disease although the exact mechanism involved is far from clear [140]. Interestingly, elevated plasma MMP-2 and -9 levels have been found in obese women and children [141,142], which imply that MMPs are potentially involved in obesity-associated heart disease. This notion received support from the evidence of an animal study published in 2001 by Peterson and coworkers who found that the MMP-2 activity in the left ventricle was elevated in obese, spontaneously hypertensive heart failure (SHHF) rats, which paralleled impaired ventricular function.
The Role of Molecular and Hormonal Factors in Obesity and the Effects of Physical Activity in Children
2022, International Journal of Molecular Sciences