ScholarlyCommons

Title

Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-1α (SDF) Generates an Effective and Translatable Angiogenic Polypeptide Analog

Author(s)

William Hiesinger
Jose Manuel Perez Aguilar, University of PennsylvaniaFollow
Pavan Atluri
Nicole A. Marotta
John R. Frederick
J Raymond Fitzpatrick
Ryan C. McCormick
Jeffrey R. Muenzer
Elaine C. Yang
Rebecca D. Levit
Li-Jun Yuan
John W. Macarthur
Jeffery G. Saven, University of PennsylvaniaFollow
Y Joseph Woo

Document Type

Journal Article

Date of this Version

9-13-2011

Publication Source

Circulation

Volume

124

Issue

11 Suppl

Start Page

18

Last Page

26

DOI

10.1161/CIRCULATIONAHA.110.009431

Abstract

BACKGROUND: Experimentally, exogenous administration of recombinant stromal cell-derived factor-1α (SDF) enhances neovasculogenesis and cardiac function after myocardial infarction. Smaller analogs of SDF may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and potential modulated delivery via engineered biomaterials. In this study, computational protein design was used to create a more efficient evolution of the native SDF protein.

METHODS AND RESULTS: Protein structure modeling was used to engineer an SDF polypeptide analog (engineered SDF analog [ESA]) that splices the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a diproline segment designed to limit the conformational flexibility of the peptide backbone and retain the relative orientation of these segments observed in the native structure of SDF. Endothelial progenitor cells (EPCs) in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared with both SDF and control gradients. EPC receptor activation was evaluated by quantification of phosphorylated AKT, and cells treated with ESA yielded significantly greater phosphorylated AKT levels than SDF and control cells. Angiogenic growth factor assays revealed a distinct increase in angiopoietin-1 expression in the ESA- and SDF-treated hearts. In addition, CD-1 mice (n=30) underwent ligation of the left anterior descending coronary artery and peri-infarct intramyocardial injection of ESA, SDF-1α, or saline. At 2 weeks, echocardiography demonstrated a significant gain in ejection fraction, cardiac output, stroke volume, and fractional area change in mice treated with ESA compared with controls.

CONCLUSIONS: Compared with native SDF, a novel engineered SDF polypeptide analog (ESA) more efficiently induces EPC migration and improves post-myocardial infarction cardiac function and thus offers a more clinically translatable neovasculogenic therapy.

Copyright/Permission Statement

This is a non-final version of an article published in final form in Circulation. 2011 September 13; 124(11 0): S18–S26. doi:10.1161/CIRCULATIONAHA.110.009431

Keywords

Angiogenic Proteins, Animals, Cardiac Output, Cell Movement, Cells, Cultured, Chemokine CXCL12, Computational Biology, Coronary Vessels, Endothelial Cells, Male, Mice, Mice, Inbred Strains, Models, Animal, Myocardial Infarction, Neovascularization, Physiologic, Protein Engineering, Rats, Rats, Wistar, Stem Cells, Stroke Volume

Recommended Citation

Hiesinger, W., Perez Aguilar, J., Atluri, P., Marotta, N. A., Frederick, J. R., Fitzpatrick, J. R., McCormick, R. C., Muenzer, J. R., Yang, E. C., Levit, R. D., Yuan, L., Macarthur, J. W., Saven, J. G., & Woo, Y. J. (2011). Computational Protein Design to Re-Engineer Stromal Cell-Derived Factor-1α (SDF) Generates an Effective and Translatable Angiogenic Polypeptide Analog. Circulation, 124 (11 Suppl), 18-26. http://dx.doi.org/10.1161/CIRCULATIONAHA.110.009431