Cyclosporine increases ischemia-induced endothelial progenitor cell mobilization through manipulation of the CD26 system.
Cyclosporin A (CsA) improves the success rate of transplantation. The CD26/dipeptidylpeptidase IV (DPP IV) system plays a critical role in mobilizing endothelial progenitor cells (EPCs) from bone marrow. This study investigated whether CsA manipulates CD26/DPP IV activity and increases EPC mobilization. C57BL/6 mice were divided into control and CsA-treated groups. Before and after hindlimb ischemia was induced, circulating EPC number and serum levels of different cytokines were measured. Compared with the controls, CsA treatment significantly increased the blood levels of stroma-derived factor-1alpha and stem cell factor after ischemic stress (P < 0.001). The CsA group displayed a significant increase in the number of circulating EPCs (sca-1+KDR+ and c-kit+CD31+ EPCs, both P < 0.05). In vivo, CsA caused a significant increase in the numbers of EPCs incorporated into the Matrigel and ischemic limbs (P < 0.05). In the peripheral blood, CsA significantly decreased CD26+ cell numbers and attenuated the plasma CD26/DPP IV activity (P < 0.001). Furthermore, short-term CsA treatment significantly improved the perfusion of ischemic limbs and decreased the spontaneous digital amputation rate. In summary, CsA manipulates the mobilization of EPCs into the circulation via the CD26/DPP IV system. Short-term CsA treatment has beneficial effects on angiogenesis of ischemic tissues.
Wang
Chao-Hung
CH
Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, 222, Mai-Chin Road, Keelung, Taiwan. bearty@adm.cgmh.org.tw
Cherng
Wen-Jin
WJ
Yang
Ning-I
NI
Hsu
Chia-Ming
CM
Yeh
Chi-Hsiao
CH
Lan
Yii-Jenq
YJ
Wang
Jong-Shyan
JS
Verma
Subodh
S
D000818:Animals; D016026:Bone Marrow Transplantation / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005434:Flow Cytometry; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*
D016207:Cytokines; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D018819:Dipeptidyl Peptidase 4; D020782:Matrix Metalloproteinases