Subjects with familial hypercholesterolemia are characterized by an inflammatory phenotype despite long-term intensive cholesterol lowering treatment
The atherosclerotic process is driven by elevated Low-density lipoprotein (LDL)-cholesterol in combination with enhanced inflammatory responses. Several mediators participate in this complex inflammatory network including members of the tumour necrosis factor (receptor) superfamily. Familial hypercholesterolemia (FH) is associated with increased risk of developing premature atherosclerosis. Statin treatment may normalize LDL-cholesterol levels, but it is not known if the inflammatory responses are normalized in statin-treated FH patients.
In long-term statin-treated FH subjects (n=33) and healthy controls (n=10) the expression of tumour necrosis factor (receptor) superfamily related genes in peripheral blood mononuclear cells (PBMC) were analyzed by real-time quantitative RT-PCR. TNFα release was measured in PBMC from patients and controls by immunoassay.
In FH patients with normal LDL-cholesterol, after a median of 17 years of statin treatment, our major findings were: (i) Gene expression of CD137, LIGHT (lymphotoxins inducible expression, competes with HSV glycoprotein D for HVEM, a receptor expressed on T-lymphocytes), HVEM (Herpesvirus entry mediator), the two TNFα Receptors (TNFR1 and TNFR2), TNF related apoptosis inducing ligand (TRAIL) and CD40 were increased in PBMC from FH patients compared to controls. (ii) The release of TNFα in PBMC from FH patients, in response to LPS was increased compared to controls. (iii) PBMC from FH patients had enhanced spontaneous release of TNFα when incubated in the presence of control serum and in particular in the presence of FH serum.
Despite long-term statin therapy, an increased expression of several TNF related genes in PBMC isolated from FH patients was observed. Our findings may implicate a pathogenic role for inflammation and TNF related molecules in FH, and these findings suggest the possibility that novel treatment modalities beyond that of statins and lipid lowering drugs may be useful in FH subjects.
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ABSTRACT: Objective: Atherosclerosis is a multi-step process, where lipids, inflammatory and hemostatic mediators orchestrate plaque formation and progression, which subsequently may lead to myocardial infarction and ischemic stroke. Familial hypercholesterolemia (FH) is associated with increased risk of premature atherosclerosis due to the genetically determined elevated low density lipoprotein (LDL)-cholesterol seen in these individuals. Children with FH are suitable to investigate the isolated effect of elevated LDL-cholesterol on early markers of atherosclerosis. The aim of the present paper was to review the literature to summarize the findings of atherosclerotic markers in children with FH to better understand how elevated LDL-cholesterol per se promotes atherogenesis. Methods: We conducted a systematic literature search from the years 1990-2013, resulting in identification of 903 articles. In order to investigate whether intima-media thickness (IMT) is different in children with and without FH, we conducted a meta-analysis of the studies comparing FH children with a control group. Results: 37 original articles were included. Among these, 24 reported subclinical measurements, whereas other articles reported measurements of atherogenic lipids (n = 9), inflammatory markers (n = 10), hemostatic markers (n = 6) and other surrogate markers of atherosclerosis (n = 7). In the meta-analysis (n = 8), IMT was significantly thicker in children with FH than in control children (weighted mean difference 0.06, 95% confidence interval [0.01, 0.11]). Conclusion: Elevated LDL-cholesterol distinguishes children with and without FH, but these groups of children also differ in several other ways. In particular, children with FH display a variety of changes reflecting both the lipid and the inflammatory arm of atherosclerosis. The IMT-meta-analysis result strengthens the evidence of early atherosclerotic development in children with FH. In a clinical perspective, early diagnosing and treatment of children with FH is of high importance to attenuate development of the potential ongoing early atherosclerotic process in these individuals.Atherosclerosis 08/2014; 235(2):299–309. DOI:10.1016/j.atherosclerosis.2014.05.917 · 3.99 Impact Factor
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ABSTRACT: It is well known that hypercholesterolemia can lead to atherosclerosis and coronary heart disease. Adipose tissue represents an active endocrine and metabolic site, which might be involved in the development of chronic disease. Because adipose tissue is a key site for cholesterol metabolism and the presence of hypercholesterolemia has been shown to induce adipocyte cholesterol overload, it is critical to investigate the role of hypercholesterolemia on normal adipose function. Studies in preadipocytes revealed that cholesterol accumulation can impair adipocyte differentiation and maturation by affecting multiple transcription factors. Hypercholesterolemia has been observed to cause adipocyte hypertrophy, adipose tissue inflammation, and disruption of endocrine function in animal studies. Moreover, these effects can also be observed in obesity-independent conditions as confirmed by clinical trials. In humans, hypercholesterolemia disrupts adipose hormone secretion of visfatin, leptin, and adiponectin, adipokines that play a central role in numerous metabolic pathways and regulate basic physiologic responses such as appetite and satiety. Remarkably, treatment with cholesterol-lowering drugs has been shown to restore adipose tissue endocrine function. In this review the role of hypercholesterolemia on adipose tissue differentiation and maturation, as well as on hormone secretion and physiologic outcomes, in obesity and non–obesity conditions is presented.Advances in Nutrition 09/2014; 5(5):497-502. DOI:10.3945/an.114.005934 · 4.71 Impact Factor
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ABSTRACT: In addition to inducing tumor cell apoptosis, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows broad biological functions both in vitro and in vivo. TRAIL gene deletion enhanced atherogenesis in hyperlipidemic mice, supporting that endogenous TRAIL has protective actions in maintaining blood vessel homeostasis and repressing atherosclerosis. The mechanisms of this beneficial effect are not understood. It remains to be determined whether the athero-protective action of TRAIL is via direct impacts on residential vascular cells or indirectly by modulating systemic immune functions. However, in vitro experiments indicate that excessive TRAIL may stimulate endothelial cell apoptosis, smooth muscle proliferation and migration, and inflammatory responses. Moreover, TRAIL can stimulate lipid uptake and foam cell formation in cultured macrophages. Here we provide a critical review on the potential relationships between TRAIL and atherosclerosis. We propose that increased TRAIL production may also have potential detrimental effects on vascular inflammation and atherosclerosis. Further in vivo experiments are warranted to elucidate the effects of exogenous TRAIL on atherogenesis.Vascular Pharmacology 11/2014; 63(3). DOI:10.1016/j.vph.2014.10.004 · 3.64 Impact Factor