Document Detail

Spliced stromal cell-derived factor-1α analog stimulates endothelial progenitor cell migration and improves cardiac function in a dose-dependent manner after myocardial infarction.
MedLine Citation:
PMID:  20951261     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: Stromal cell-derived factor (SDF)-1α is a potent endogenous endothelial progenitor cell (EPC) chemokine and key angiogenic precursor. Recombinant SDF-1α has been demonstrated to improve neovasculogenesis and cardiac function after myocardial infarction (MI) but SDF-1α is a bulky protein with a short half-life. Small peptide analogs might provide translational advantages, including ease of synthesis, low manufacturing costs, and the potential to control delivery within tissues using engineered biomaterials. We hypothesized that a minimized peptide analog of SDF-1α, designed by splicing the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a truncated amino acid linker, would induce EPC migration and preserve ventricular function after MI.
METHODS: EPC migration was first determined in vitro using a Boyden chamber assay. For in vivo analysis, male rats (n = 48) underwent left anterior descending coronary artery ligation. At infarction, the rats were randomized into 4 groups and received peri-infarct intramyocardial injections of saline, 3 μg/kg of SDF-1α, 3 μg/kg of spliced SDF analog, or 6 μg/kg spliced SDF analog. After 4 weeks, the rats underwent closed chest pressure volume conductance catheter analysis.
RESULTS: EPCs showed significantly increased migration when placed in both a recombinant SDF-1α and spliced SDF analog gradient. The rats treated with spliced SDF analog at MI demonstrated a significant dose-dependent improvement in end-diastolic pressure, stroke volume, ejection fraction, cardiac output, and stroke work compared with the control rats.
CONCLUSIONS: A spliced peptide analog of SDF-1α containing both the N- and C- termini of the native protein induced EPC migration, improved ventricular function after acute MI, and provided translational advantages compared with recombinant human SDF-1α.
William Hiesinger; John R Frederick; Pavan Atluri; Ryan C McCormick; Nicole Marotta; Jeffrey R Muenzer; Y Joseph Woo
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of thoracic and cardiovascular surgery     Volume:  140     ISSN:  1097-685X     ISO Abbreviation:  J. Thorac. Cardiovasc. Surg.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-18     Completed Date:  2010-11-08     Revised Date:  2013-02-05    
Medline Journal Info:
Nlm Unique ID:  0376343     Medline TA:  J Thorac Cardiovasc Surg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1174-80     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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MeSH Terms
Cardiac Output / drug effects
Cardiotonic Agents / administration & dosage,  chemical synthesis,  pharmacology*
Cell Movement / drug effects*
Cells, Cultured
Chemokine CXCL12 / administration & dosage,  chemistry,  pharmacology*
Disease Models, Animal
Dose-Response Relationship, Drug
Endothelial Cells / drug effects*,  metabolism
Green Fluorescent Proteins / biosynthesis,  genetics
Hemodynamics / drug effects
Injections, Intralesional
Myocardial Infarction / drug therapy*,  physiopathology
Peptides / administration & dosage,  chemical synthesis,  pharmacology*
Protein Conformation
Protein Engineering
Protein Structure, Tertiary
Rats, Inbred Lew
Rats, Transgenic
Rats, Wistar
Recombinant Proteins / administration & dosage
Stem Cells / drug effects*,  metabolism
Stroke Volume / drug effects
Time Factors
Ventricular Function, Left / drug effects*
Grant Support
1R01HL089315-01/HL/NHLBI NIH HHS; K08 HL072812/HL/NHLBI NIH HHS; T32 HL007843/HL/NHLBI NIH HHS; T32 HL007843-14/HL/NHLBI NIH HHS; T32-HL-007843-13/HL/NHLBI NIH HHS
Reg. No./Substance:
0/CXCL12 protein, human; 0/Cardiotonic Agents; 0/Chemokine CXCL12; 0/Peptides; 0/Recombinant Proteins; 147336-22-9/Green Fluorescent Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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