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    
Abstract/OtherAbstract:
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.
Authors:
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.
Affiliation:
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
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
Humans
Injections, Intralesional
Male
Myocardial Infarction / drug therapy*,  physiopathology
Peptides / administration & dosage,  chemical synthesis,  pharmacology*
Protein Conformation
Protein Engineering
Protein Structure, Tertiary
Rats
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
ID/Acronym/Agency:
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
Chemical
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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