Protease-resistant stromal cellderived factor-1 for the treatment of experimental peripheral artery disease

Segers, Vincent F.M.; Revin, Vyacheslav; Wu, Weitao; Qiu, Helen; Yan, Zheng; Lee, Richard T.; Sandrasagra, Anthony

doi:10.1161/CIRCULATIONAHA.110.991786

Title

Protease-resistant stromal cellderived factor-1 for the treatment of experimental peripheral artery disease

Author

Segers, Vincent F.M.

Revin, Vyacheslav

Wu, Weitao

Qiu, Helen

Yan, Zheng

Lee, Richard T.

Sandrasagra, Anthony

Abstract

BackgroundPeripheral artery disease is a potentially incapacitating disease for which pharmacological options are limited. Stromal cellderived factor-1 (SDF-1) is a chemokine that attracts endothelial progenitor cells and promotes angiogenesis. Therapeutic use of SDF-1 in hindlimb ischemia may be challenged by proteolytic degradation. We hypothesized that protease-resistant variants of SDF-1 can increase blood flow in an experimental model of hindlimb ischemia. Methods and ResultsWe screened a peptide library for mutations in SDF-1 that provide resistance to matrix metalloproteinase cleavage. Recombinant SDF-1 proteins carrying the mutations were designed, expressed, and purified, and activity of mutant proteins was tested with receptor activation assays and in vivo Matrigel plug assays. SSDF-1(S4V), which is resistant to both dipeptidylpeptidase IV/CD26 and matrix metalloproteinase-2 cleavage, was active in vitro and induced angiogenesis in vivo. We then designed and purified fusion proteins of SSDF-1 and SSDF-1(S4V) with the sequence of self-assembling peptide nanofibers for incorporation into nanofibers. In a blinded and randomized hindlimb ischemia mouse study, SSDF-1(S4V) delivery by nanofibers improved blood flow as measured by laser Doppler from 23.1±1.9% (untreated control) to 55.1±5.7% 6 weeks after surgery (P<0.001). Nanofibers alone or SSDF-1 delivered by nanofibers did not improve blood flow. Furthermore, SSDF-1(S4V) delivered by nanofibers increased formation of new arterioles. In vitro, SSDF-1(S4V) attracts smooth muscle cells but does not induce mitosis. ConclusionsSDF-1 engineered to be resistant to dipeptidylpeptidase IV/CD26 and matrix metalloproteinase-2 cleavage and delivered by nanofibers improves blood flow in a model of peripheral artery disease.

Language

English

Source (journal)

Circulation / American Heart Association. - New York, N.Y.

Publication

New York, N.Y. : 2011

ISSN

0009-7322

DOI

10.1161/CIRCULATIONAHA.110.991786

Volume/pages

123 :12 (2011) , p. 1306-1315