PMID- 22509290
OWN - NLM
STAT- MEDLINE
DCOM- 20120820
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 4
DP  - 2012
TI  - Distinct effects of unfractionated heparin versus bivalirudin on circulating 
      angiogenic peptides.
PG  - e34344
LID - 10.1371/journal.pone.0034344 [doi]
LID - e34344
AB  - BACKGROUND: Human studies of therapeutic angiogenesis, stem-cell, and 
      progenitor-cell therapy have failed to demonstrate consistent clinical benefit. 
      Recent studies have shown that heparin increases circulating levels of 
      anti-angiogenic peptides. Given the widely prevalent use of heparin in 
      percutaneous and surgical procedures including those performed as part of studies 
      examining the benefit of therapeutic angiogenesis and cell-based therapy, we 
      compared the effects of unfractionated heparin (UFH) on angiogenic peptides with 
      those of bivalirudin, a relatively newer anticoagulant whose effects on 
      angiogenic peptides have not been studied. METHODOLOGY/PRINCIPAL FINDINGS: We 
      measured soluble fms-like tyrosine kinase-1 (sFLT1), placental growth factor 
      (PlGF), vascular endothelial growth factor (VEGF), and soluble Endoglin (sEng) 
      serum levels by enzyme linked immunosorbent assays (ELISA) in 16 patients 
      undergoing elective percutaneous coronary intervention. Compared to baseline 
      values, sFLT1 and PlGF levels increased by 2629+/-313% and 253+/-54%, respectively, 
      within 30 minutes of UFH therapy (p<0.01 for both; n = 8). VEGF levels decreased 
      by 93.2+/-5% in patients treated with UFH (p<0.01 versus baseline). No change in 
      sEng levels were observed after UFH therapy. No changes in sFLT1, PlGF, VEGF, or 
      sEng levels were observed in any patients receiving bivalirudin (n = 8). To 
      further explore the direct effect of anticoagulation on circulating angiogenic 
      peptides, adult, male wild-type mice received venous injections of clinically 
      dosed UFH or bivalirudin. Compared to saline controls, sFLT1 and PlGF levels 
      increased by >500% (p<0.01, for both) and VEGF levels increased by 221+/-101% 
      (p<0.05) 30 minutes after UFH treatment. Bivalirudin had no effect on peptide 
      levels. To study the cellular origin of peptides after anticoagulant therapy, 
      human coronary endothelial cells were treated with UFH and demonstrated increased 
      sFLT1 and PlGF levels (ANOVA p<0.01 for both) with reduced VEGF levels (ANOVA 
      p<0.05). Bivalirudin had no effect on peptide levels in vitro. 
      CONCLUSIONS/SIGNIFICANCE: Circulating levels of sFLT1, PlGF, and VEGF are 
      significantly altered by UFH, while bivalirudin therapy has no effect. These 
      findings may have significant implications for clinical studies of therapeutic 
      angiogenesis, stem-cell and progenitor-cell therapy.
FAU - Kapur, Navin K
AU  - Kapur NK
AD  - Molecular Cardiology Research Institute, Tufts Medical Center, Boston, 
      Massachusetts, United States of America. nkapur@tuftsmedicalcenter.org
FAU - Shenoy, Chetan
AU  - Shenoy C
FAU - Yunis, Adil A
AU  - Yunis AA
FAU - Mohammad, Najwa N
AU  - Mohammad NN
FAU - Wilson, Szuhuei
AU  - Wilson S
FAU - Paruchuri, Vikram
AU  - Paruchuri V
FAU - Mackey, Emily E
AU  - Mackey EE
FAU - Qiao, Xiaoying
AU  - Qiao X
FAU - Shah, Ameer
AU  - Shah A
FAU - Esposito, Michele L
AU  - Esposito ML
FAU - Karas, Richard H
AU  - Karas RH
FAU - Jaffe, Iris Z
AU  - Jaffe IZ
LA  - eng
GR  - K08 HL094909/HL/NHLBI NIH HHS/United States
GR  - R01 HL095590/HL/NHLBI NIH HHS/United States
PT  - Clinical Trial
PT  - Comparative Study
PT  - Journal Article
DEP - 20120411
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Angiogenic Proteins)
RN  - 0 (Anticoagulants)
RN  - 0 (Hirudins)
RN  - 0 (Peptide Fragments)
RN  - 0 (Recombinant Proteins)
RN  - 9005-49-6 (Heparin)
RN  - TN9BEX005G (bivalirudin)
SB  - IM
MH  - Angiogenic Proteins/*blood/metabolism
MH  - Animals
MH  - Anticoagulants/*pharmacology
MH  - Coronary Vessels/cytology
MH  - Endothelial Cells/drug effects/metabolism
MH  - Female
MH  - Heparin/*chemistry/*pharmacology
MH  - Hirudins/*pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Peptide Fragments/*pharmacology
MH  - Recombinant Proteins/pharmacology
MH  - Time Factors
PMC - PMC3324508
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/04/18 06:00
MHDA- 2012/08/21 06:00
PMCR- 2012/04/11
CRDT- 2012/04/18 06:00
PHST- 2011/11/16 00:00 [received]
PHST- 2012/02/27 00:00 [accepted]
PHST- 2012/04/18 06:00 [entrez]
PHST- 2012/04/18 06:00 [pubmed]
PHST- 2012/08/21 06:00 [medline]
PHST- 2012/04/11 00:00 [pmc-release]
AID - PONE-D-11-23026 [pii]
AID - 10.1371/journal.pone.0034344 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(4):e34344. doi: 10.1371/journal.pone.0034344. Epub 2012 Apr 11.