title: Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells.
abstract: BACKGROUND
  Kallistatin exerts pleiotropic activities in inhibiting inflammation, apoptosis, and oxidative stress in endothelial cells. Because endothelial progenitor cells (EPCs) play a significant role in vascular repair, we investigated whether kallistatin contributes to vascular regeneration by enhancing EPC migration and function.
  
  
  RESULTS
  We examined the effect of endogenous kallistatin on circulating EPCs in a rat model of vascular injury and the mechanisms of kallistatin on EPC mobility and function in vitro. In deoxycorticosterone acetate-salt hypertensive rats, we found that kallistatin depletion augmented glomerular endothelial cell loss and diminished circulating EPC number, whereas kallistatin gene delivery increased EPC levels. In cultured EPCs, kallistatin significantly reduced tumor necrosis factor-α-induced apoptosis and caspase-3 activity, but kallistatin's effects were blocked by phosphoinositide 3-kinase inhibitor (LY294002) and nitric oxide (NO) synthase inhibitor (l-NAME). Kallistatin stimulated the proliferation, migration, adhesion and tube formation of EPCs; however, kallistatin's actions were abolished by LY294002, l-NAME, endothelial NO synthase-small interfering RNA, constitutively active glycogen synthase kinase-3β, or vascular endothelial growth factor antibody. Kallistatin also increased Akt, glycogen synthase kinase-3β, and endothelial NO synthase phosphorylation; endothelial NO synthase, vascular endothelial growth factor, and matrix metalloproteinase-2 synthesis and activity; and NO and vascular endothelial growth factor levels. Kallistatin's actions on phosphoinositide 3-kinase-Akt signaling were blocked by LY294002, l-NAME, and anti-vascular endothelial growth factor antibody.
  
  
  CONCLUSIONS
  Endogenous kallistatin plays a novel role in protection against vascular injury in hypertensive rats by promoting the mobility, viability, and vasculogenic capacity of EPCs via enhancing NO and vascular endothelial growth factor levels through activation of phosphoinositide 3-kinase-Akt signaling. Kallistatin therapy may be a promising approach in the treatment of vascular diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Lin
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Pengfei
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Jingmei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Hagiwara
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Bo
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Grant
authors.initials: G
authors.lastname: Bledsoe
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, Medical University of South Carolina, Charleston, SC (E.C.).
authors.forename: Eugene
authors.initials: E
authors.lastname: Chang
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC (L.G., P.L., J.Z., M.H., B.S., G.B., L.C., J.C.).
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000378:metabolism* / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology*; D005434:Flow Cytometry; D066298:In Vitro Techniques; D008297:Male; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D015843:Serpins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D015843:Serpins; C051324:kallistatin
keywords: angiogenesis; apoptosis; endothelial progenitor cells; kallistatin; nitric oxide