Abstract
Background-Endothelial injury is considered critical for progression of atherosclerosis and its complications in coronary artery disease (CAD). The endothelial-supportive effects of bradykinin have mainly been attributed to activation of the resident endothelium. Here we newly investigate the role of bradykinin and its B2 receptor for the recruitment and functional activation of circulating mononuclear cell subsets with endothelial-repair promoting capacity, such as CD34(+)CXCR4(+)cells, at sites of arterial injury.
Methods and Results-Bradykinin-B2-receptor (B2R) blockade by icatibant substantially impaired recruitment of circulating CD34(+)CXCR4(+) mononuclear cells (expressing high levels of B2R) to endothelial cells in vitro and to injured arterial wall in vivo, whereas recruitment of CD14(hi) monocytes (expressing low levels of B2R) was unchanged. Moreover, the capacity of genetically B2R-deficient bone marrow cells to promote endothelial repair in vivo was markedly impaired as compared with wild-type bone marrow cells. B2R expression was reduced on CD34(+)CXCR4(+) mononuclear cells and endothelial repair-promoting early outgrowth cells, but not on CD14(hi)monocytes, from CAD patients as compared with healthy subjects. B2R stimulation induced CD18 activation in early outgrowth cells of healthy subjects, but not in early outgrowth cells of CAD patients. Adenoviral B2R overexpression enhanced in vivo vascular recruitment and rescued impaired endothelial repair capacity of early outgrowth cells from CAD patients.
Conclusions-We newly report that bradykinin/B2R signaling may promote endothelial repair after arterial injury by selective recruitment and functional activation of B2R-expressing circulating mononuclear cell subsets. In CAD patients, B2R downregulation on endothelial repair-promoting circulating mononuclear cells substantially impairs the bradykinin-dependent endothelial repair, representing a novel mechanism promoting endothelial injury in CAD patients. (Circulation. 2013;127:594-603.)
Original language | English |
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Pages (from-to) | 594-603 |
Number of pages | 10 |
Journal | Circulation |
Volume | 127 |
Issue number | 5 |
Early online date | 30 Dec 2012 |
DOIs | |
Publication status | Published - 5 Feb 2013 |
Keywords
- Animals
- Antigens, CD14
- Antigens, CD34
- Bradykinin
- Case-Control Studies
- Cell Adhesion
- Cells, Cultured
- Coronary Disease
- Down-Regulation
- Endothelium, Vascular
- Female
- Humans
- Leukocytes, Mononuclear
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Middle Aged
- Models, Animal
- Receptor, Bradykinin B2
- Receptors, CXCR4
- Signal Transduction