Peripheral Artery Disease Is Associated With a High CD163/TWEAK Plasma Ratio

Abstract

Objective-In addition to its role in the clearance of haptoglobin-hemoglobin (Hp-Hb) complexes, CD163 is a macrophage scavenger receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK). We recently reported that the CD163/TWEAK plasma ratio could be a potential biomarker of atherothrombosis in asymptomatic subjects. In this study, we assessed soluble TWEAK (sTWEAK) and soluble CD163 (sCD163) plasma levels in white males with peripheral artery disease (PAD) and in atherothrombotic femoral plaques to evaluate their relationship with disease. We also analyzed whether Hp-Hb complexes could compete for CD163-mediated TWEAK uptake. Methods and Results-Patients with PAD (nϭ155) showed a trend toward lower sTWEAK (median [interquartile range]:134 [110 -204] [234 -369] ng/mL; PϽ0.001) plasma concentrations than age-matched controls (nϭ251). sCD163 and sTWEAK plasma levels were negatively correlated in both patients and controls. After stratification according to the severity of disease, sCD163/sTWEAK ratio was significantly increased in patients with more severe disease relative to the other groups (Pϭ0.049). Analysis of conditioned medium obtained from cultured human atherothrombotic femoral plaque samples (nϭ36) and healthy aortas (nϭ14) revealed that high amounts of sCD163 were released by the atherothrombotic tissue, whereas sTWEAK presented the opposite trend (PϽ0.05). Finally, we report a potential association between CD163 shedding and oxidative stress. Conclusion-Our results suggest that the sCD163/sTWEAK plasma ratio may be associated with atherothrombosis burden in PAD. We hypothesize that an imbalance between TWEAK and CD163 could reflect the progression of atherothrombosis. Key Words: atherosclerosis Ⅲ cytokines Ⅲ hemoglobin Ⅲ macrophages Ⅲ peripheral arterial disease P eripheral artery disease (PAD) is an important manifestation of atherothrombosis 1,2 in which several proinflammatory cytokines are increased. [3][4][5][6] Cytokine-mediated monocyte recruitment and differentiation into macrophages play a key role in atherothrombotic lesion progression and vulnerability. [7][8][9] However, recent evidence describes atheroprotective properties of a subtype of macrophages (type II) able to scavenge haptoglobin-hemoglobin (Hp-Hb) complexes via the CD163 receptor from lesions with intraplaque hemorrhage. 10,11 Intraplaque hemorrhage is a common event in advanced atherothrombotic lesions. 12 Hemolysis of extravasated red blood cells leads to accumulation of pro-oxidant Hb. 13 CD163 is expressed mainly at the membrane of resident tissue macrophages; however, a soluble form of the protein (sCD163) has also been identified in both human plasma and cell culture supernatants, 14 resulting from a proteolytic cleavage of the cell surface protein. 15 sCD163 plasma levels are increased in diseases associated with macrophage activation, including coronary artery disease. 16 CD163 has been recently described as a scavenger receptor for tumor necrosis factorlike weak inducer of apoptosis (TWEAK); this prov...

Soluble TWEAK and PTX3 in Nondialysis CKD Patients

“…Fn14 expression is practically absent in healthy human aortic wall but is highly increased under pathologic conditions (37). A pro-inflammatory environment increases Fn14 expression (35,36) but also allows CD163 to sequester and degrade sTWEAK by acting as a scavenger receptor (38), thus preventing Fn14 binding (39). On the basis of this preceding literature, we speculate that the reduction in sTWEAK concentrations across CKD stages observed in our crosssectional study could potentially reflect either of these two processes.…”

The role of tumor necrosis factor-like weak inducer of apoptosis in atherosclerosis via its two different receptors

“…Additionally, these patients exhibited a significantly increased sCD163/sTWEAK ratio that was positively correlated with the severity of their diseases (91). Accordingly, the sCD163/sTWEAK ratio may act as an indicator of atherothrombosis progression (91). Similar results were revealed in other atherosclerotic related diseases such as coronary artery disease with or without chronic kidney disease (19,20,58).…”

“…Additionally, these patients exhibited a significantly increased sCD163/sTWEAK ratio that was positively correlated with the severity of their diseases (91). Accordingly, the sCD163/sTWEAK ratio may act as an indicator of atherothrombosis progression (91).…”

“…Moreno et al (91) observed that sCD163 and sTWEAK levels were negatively correlated in cultured human atherothrombotic femoral plaque samples and patients with atherothrombosis-derived peripheral artery diseases. Additionally, these patients exhibited a significantly increased sCD163/sTWEAK ratio that was positively correlated with the severity of their diseases (91).…”

The association of high sCD163/sTWEAK ratio with cardiovascular disease in hemodialysis patients

“…sCD163 levels are increased and associated with ATS severity in CKD [20], but also in obese and hypertensive patients [21]. In addition, sCD163/sTWEAK ratio was described as a potential ATS biomarker in asymptomatic peripheral artery disease patients as it is associated with incipient atherothrombosis [22].…”