Measurement of the soluble angiopoietin receptor tie-2 in patients with coronary artery disease: development and application of an immunoassay.
BACKGROUND
The angiopoietin family has emerged as a group of crucial growth factors to normal angiogenesis. They are essential to the development of the mature vessel wall and interact with the endothelium via endothelial cell-specific tyrosine kinase receptors, tie-1 and tie-2. The role of the tie-2 receptor has been extensively examined in neovascularization associated with malignancy, but little is known about the role it may play in atherosclerosis, a condition whose pathophysiology also involves angiogenesis. Soluble tie-2 has been detected in the plasma of healthy controls, but this has yet to be applied to patients in the clinical setting.


METHODS
We developed an ELISA to detect plasma tie-2 levels and applied these to a clinical setting. The intra- and interassay coefficients of variation for the assay were 4.7% and 9.6%, respectively. We then measured levels of tie-2, vascular endothelial growth factor (VEGF), another factor associated with angiogenesis, and the soluble VEGF receptor Flt-1 (sFlt-1) in 75 patients with coronary artery disease [25 with acute myocardial infarction (AMI), 25 with acute coronary syndromes (ACS) and 25 with stable angina] and 25 healthy controls.


RESULTS
Median [IQR, interquartile range] levels of tie-2 were significantly higher in the coronary artery disease patients (AMI 12 [10-17] ng mL-1, ACS 10 [9-14] ng mL-1, stable angina 9 [3-11] ng mL-1) when compared with the controls (7.5 [7-9] ng mL-1P = 0.004). As expected, levels of VEGF and sFlt were significantly different from those in the healthy controls (P = 0.011 and P < 0.001, respectively). Significant correlations were found between levels of tie-2 and VEGF (Spearman r = 0.59, P < 0.001), tie-2 and sFlt-1 (r = 0.45, P < 0.001) and VEGF and sFlt-1 (r = 0.56, P < 0.001) in the whole study group.


CONCLUSIONS
We suggest that tie-2 may be potentially used as a marker of angiogenesis in atherosclerosis and may help elucidate the role of the angiopoietin/tie-2 system in atherogenesis.
Chung
N A Y
NA
Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham B18 7QH, UK.
Makin
A J
AJ
Lip
G Y H
GY
D000368:Aged; D043925:Angiogenesis Inducing Agents / Q000097:blood*; D042702:Angiopoietin-2; D003324:Coronary Artery Disease / Q000097:blood* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000097:blood*; D004791:Enzyme Inhibitors / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood*; D008222:Lymphokines / Q000097:blood*; D008297:Male; D008875:Middle Aged; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D043925:Angiogenesis Inducing Agents; D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors