Distinct kinin-induced functions are altered in circulating cells of young type 1 diabetic patients.
OBJECTIVE
We aimed to understand early alterations in kinin-mediated migration of circulating angio-supportive cells and dysfunction of kinin-sensitive cells in type-1 diabetic (T1D) patients before the onset of cardiovascular disease.


METHODS
Total mononuclear cells (MNC) were isolated from peripheral blood of 28 T1D patients free from cardiovascular complications except mild background retinopathy (age: 34.8+/-1.6 years, HbA(1C): 7.9+/-0.2%) and 28 age- and sex-matched non-diabetic controls (H). We tested expression of kinin receptors by flow cytometry and migratory capacity of circulating monocytes and progenitor cells towards bradykinin (BK) in transwell migration assays. MNC migrating towards BK (BK(mig)) were assessed for capacity to support endothelial cell function in a matrigel assay, as well as generation of nitric oxide (NO) and superoxide (O(2) (-)*) by using the fluorescent probes diaminofluorescein and dihydroethidium.


RESULTS
CD14(hi)CD16(neg), CD14(hi)CD16(pos) and CD14(lo)CD16(pos) monocytes and circulating CD34(pos) progenitor cells did not differ between T1D and H subjects in their kinin receptor expression and migration towards BK. T1D BK(mig) failed to generate NO upon BK stimulation and supported endothelial cell network formation less efficiently than H BK(mig). In contrast, O(2) (-)* production was similar between groups. High glucose disturbed BK-induced NO generation by MNC-derived cultured angiogenic cells.


CONCLUSIONS
Our data point out alterations in kinin-mediated functions of circulating MNC from T1D patients, occurring before manifest macrovascular damage or progressed microvascular disease. Functional defects of MNC recruited to the vessel wall might compromise endothelial maintenance, initially without actively promoting endothelial damage, but rather by lacking supportive contribution to endothelial regeneration and healing.
Kränkel
Nicolle
N
Experimental Cardiovascular Medicine, University of Bristol, Bristol, UK. n.kraenkel@gmx.de
Armstrong
Stephen Paul
SP
McArdle
Craig Alexander
CA
Dayan
Colin
C
Madeddu
Paolo
P
D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007705:Kinins / Q000502:physiology*; D008297:Male; D009000:Monocytes / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism
D001786:Blood Glucose; D007705:Kinins; D013481:Superoxides; D009569:Nitric Oxide