Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia
Introduction
Familial hypercholesterolemia (FH) is a common autosomal dominantly inherited disorder of lipid/cholesterol metabolism whose origins involve either mutations in the low-density lipoprotein (LDL) receptor gene or in the gene encoding apolipoprotein B or the in PCSK9 gene [1], [2], [3], [4]. As a result of the disruption of LDL receptor function, patients with FH display markedly elevated circulating levels of LDL cholesterol from birth, ranging from 7 to 15 mmol/l in heterozygous patients to up to move than 25 mmol/l in the homozygous state. As high levels of LDL-cholesterol are a major risk factor for cardiovascular disease (CAD), FH subjects exhibit a significantly increased risk of premature CAD, due to the formation of atherosclerotic lesions in childhood [5], [6].
Atherosclerosis is recognized as a chronic inflammatory disease of the arterial wall in which an inflammatory response is a key event that leads to the formation of atheromatous lesions [7]. Fragilisation of the fibrous cap of atherosclerotic plaques is intimately related to the presence of an inflammatory state which plays a crucial role in plaque rupture, the major pathophysiological event underlying acute coronary syndromes [8], [9], [10]. Expression of a spectrum of inflammatory factors, such as C-reactive protein (CRP) and proinflammatory cytokines including TNF-α and IL-18, constitutes a strong link between inflammation and atherogenesis in coronary artery disease [11]. Proinflammatory cytokines are responsible for vascular endothelial dysfunction and activation, leading for example to the overexpression of endothelial adhesion molecules [12], to enhanced uptake of oxidized LDL through increased expression of scavenger receptors in monocyte-derived macrophages [13], to plaque fragilisation [14] and to induction of cell proliferation in the arterial wall [15]. The matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs) constitute an additional group of biomarkers and of actors in the inflammatory process, and play a central role in subendothelial vascular extracellular matrix remodeling [16], [17], [18]. Experimental data have established that MMPs and TIMPs are involved in the development of atherosclerotic lesions and their fragilisation [16], [17], [18], [19]; moreover, we recently observed that asymptomatic hyperlipidemic subjects at high cardiovascular risk display elevated circulating levels of MMP-3, MMP-9 and TIMP-1 [20].
There is a paucity of information on the inflammatory state in untreated FH subjects, and more specifically on circulating levels of cytokines, MMPs and TIMPs [21], [22]. However, although the cause of FH is monogenic, wide variation exists in the onset and severity of atherosclerotic disease in these patients [23]. We hypothesized that comprehensive evaluation of the inflammatory state of never-treated FH patients might provide not only further insight into variation in disease severity but might also improve cardiovascular risk assessment. We therefore determined serum levels of several inflammatory markers, i.e. high sensitive CRP (hs-CRP), IL-18 and tumor necrosis factor (TNF)-α, and of matrix remodeling factors, i.e. MMP-3, MMP-9 and TIMP-1, in homozygous FH patients who had never received either lipid-lowering or anti-inflammatory treatment. We equally evaluated the potential relationships between these inflammatory molecules and the plasma lipid profile.
Section snippets
Patients
Three groups of Moroccan subjects were studied: 4 homozygous FH subjects (M/F ratio: 3/1; age: 16.2 ± 8.0 years, mean ± SD); 7 heterozygous FH subjects (M/F ratio: 5/2; age: 42.5 ± 22.6 years), and 5 healthy control subjects (M/F ratio: 3/2; age: 24.2 ± 7.2 years). The diagnosis of FH was established using Simon Broome's criteria [24] and confirmed by the presence of LDL receptor gene mutation. The control subjects and FH patients are issued from 3 unrelated families with distinct LDL receptor gene
Results
Serum lipid and lipoprotein levels are summarized in Table 1. As expected, TC and TG were significantly elevated in both homozygous and heterozygous FH patients as compared to non-FH controls of the same ethnicity, but to a greater extent in the homozygous than in the heterozygous FH patient group (p < 0.001 and p < 0.05 for TC and TG, respectively). Levels of HDL-C were markedly decreased In homozygous patients (p < 0.05), while LDL-C and Apo B levels were markedly increased (p < 0.001). Finally,
Discussion
In the present study, we demonstrate for the first time that never-treated homozygous FH patients exhibited elevated circulating levels of the proinflammatory cytokine IL-18, the inflammatory marker and factor hs-CRP, and the matrix remodeling mediators MMP-9 and TIMP-1, as compared to normolipidemic control subjects of the same ethnicity.
Atherosclerosis is characterized by chronic inflammation of the arterial wall at lesion sites, as well as by activation of vascular endothelial cells, smooth
Acknowledgements
This work was supported by the Coopération Maroco-Française en Recherche Médicale (Accord CNCPRST-INSERM), by INSERM and Assistance Publique-Hôpitaux de Paris (contrat Interface).
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Children with familial hypercholesterolemia are characterized by an inflammatory imbalance between the tumor necrosis factor α system and interleukin-10
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