Sonic hedgehog is a potent chemoattractant for human monocytes: diabetes mellitus inhibits Sonic hedgehog-induced monocyte chemotaxis.
The aim of the present study was to evaluate the expression of hedgehog (Hh) signaling molecules and the chemotactic activity of Sonic hedgehog (Shh) in monocytes from control (CTR) and diabetic patients with or without coronary artery disease (CAD). Previously several studies demonstrated that exogenous administration of Shh can induce angiogenesis and accelerate repair of ischemic myocardium and skeletal muscles. Blood samples were collected from (1) CTR (n = 25); (2) patients with stable CAD without diabetes mellitus (CAD-DM, n = 10); and (3) with stable CAD with DM (CAD+DM, n = 15). Monocytes were isolated by Percoll gradient and subjected to PCR and chemotaxis analysis. Hh signaling molecules were expressed in human monocytes, and Shh-induced monocyte chemotaxis. Shh-stimulated migration of monocytes from CTR measured 172.5 +/- 90% and a maximal stimulation was observed at Shh concentration of 1 microg/ml. However, Shh failed to induce migration of monocytes from CAD+DM (94.3 +/- 27%, P < 0.001 vs. CTR). The impaired response to Shh was associated with strong transcriptional upregulation of the receptor Ptc, while expression of downstream molecules was not altered. Moreover, Ptc is strongly expressed in macrophages of human aortic atherosclerotic plaque. Thus, Shh is a potent chemoattractant for monocytes and it activates classical signaling pathways related to migration. The Shh signaling was negatively affected by DM which might be involved in the pathogenesis of DM-related complications.
Dunaeva
Marina
M
Department of Cardiology, University Hospital of Maastricht, Cardiovascular Research Institute of Maastricht (CARIM), P.Debyelaan 25, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
Voo
Stefan
S
van Oosterhoud
Carolien
C
Waltenberger
Johannes
J
D000368:Aged; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003324:Coronary Artery Disease / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000502:physiology*; D000072079:Patched Receptors; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D015398:Signal Transduction
D053823:Hedgehog Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D019869:Phosphatidylinositol 3-Kinases; D019204:GTP-Binding Proteins