人可溶性肿瘤坏死因子样细胞凋亡弱诱导因子sTWEAK， 一个代谢综合征和动脉粥样硬化之生物标示物

Identification of Soluble Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (sTWEAK) as a Possible Biomarker of Subclinical Atherosclerosis

Objectives— Assessment of vascular risk in asymptomatic patients and the response to medical therapy is a major challenge for prevention of cardiovascular events. Our aim was to identify proteins differentially released by healthy versus atherosclerotic arterial walls, which could be found in plasma and serve as markers of atherosclerosis.

Methods and Results— We have analyzed supernatants obtained from cultured human carotid plaques and healthy arteries by surface-enhanced laser-desorption/ionization time-of-flight mass spectrometry ProteinChip System. Surface-enhanced laser-desorption/ionization analysis unveiled an 18.4-kDa peak released in lower amount by carotid plaques than normal endarteries. This protein was identified as soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK). To confirm that sTWEAK was the protein of interest, Western blot and enzyme-linked immunosorbent assay were performed. Both techniques confirmed that sTWEAK levels were decreased in carotid plaque supernatants. Subsequent measurement of sTWEAK in plasma showed a reduced concentration in subjects with carotid stenosis (N=30) compared with healthy subjects matched by sex and age (N=28) (P<0.001). Furthermore, in a test population of 106 asymptomatic subjects, we showed that sTWEAK concentrations negatively correlated with the carotid intima-media thickness (r=–0.4; P<0.001), an index of subclinical atherosclerosis.

Conclusions— These results suggest that sTWEAK could be a potential biomarker of atherosclerosis.

Recently, circulating soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) was introduced as a potential biomarker which is downregulated in atherosclerosis. In the current study, we hypothesized that sTWEAK serum levels are decreased in end-stage renal disease and in patients with type 2 diabetes mellitus (T2DM) since both conditions are high-risk states for atherosclerotic disease. Soluble TWEAK was quantified by ELISA in control patients (n=60) with a glomerular filtration rate above 50ml/min and patients on chronic hemodialysis (CD, n=60) and correlated to clinical and biochemical measures of renal function, glucose, and lipid metabolism, as well as inflammation. 30 control patients and 32 CD patients presented with T2DM. Mean serum sTWEAK concentrations were significantly lower in CD and T2DM patients with lowest concentrations seen when both conditions were present (control/-T2DM: 669+/-201mug/l; control/+T2DM: 516+/-187mug/l; CD/-T2DM: 402+/-128mug/l; CD/+T2DM: 317+/-132mug/l; all comparisons between groups p<0.05). In univariate analyses, sTWEAK was negatively correlated with fasting glucose in both, control and CD patients. In multivariate analyses, CD and T2DM remained independently associated with circulating sTWEAK. Taken together, circulating sTWEAK concentrations are decreased in end-stage renal disease and T2DM. Furthermore, both conditions have an additive and independent negative effect on sTWEAK levels. Our results support the view that circulating sTWEAK might be a novel biomarker of atherosclerosis.

Kralisch S, et al. Atherosclerosis. 2007 Dec 1 [Epub ahead of print]