Publications (2)21.03 Total impact
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Article: Stromal cell-derived factor-1 retention and cardioprotection for ischemic myocardium.
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ABSTRACT: Stromal cell-derived factor-1 (SDF-1) is a chemoattractant of stem/progenitor cells, and several studies have shown that SDF-1 may improve ventricular function after infarction. SDF-1 is cleaved by proteases including matrix metalloproteinase-2 (MMP-2) and CD26/dipeptidylpeptidase-4 (DPP-4), which are activated in injured tissues. We investigated the biodistribution and functional roles of SDF-1 in experimental ischemia/reperfusion injury in rats. Radiolabeled SDF-1 given by intracoronary injection was selectively concentrated in ischemic myocardium. The enhanced uptake of SDF-1 in ischemic myocardium was not mediated by its receptor, CXCR4. Mass spectrometry and Western analyses showed that SDF-1 was cleaved by DPP-4 in plasma and myocardium, whereas a bioengineered MMP-2/DPP-4-resistant form of SDF-1, SSDF-1(S4V), was highly stable. A single dose of SSDF-1(S4V) exhibited greater potency for cardioprotection than wild-type SDF-1. SSDF-1(S4V) improved cardiac function in rats even after a 3-hour ischemic period. These results show that a single dose of protease-resistant SSDF-1(S4V) after myocardial infarction leads to dramatic improvement in angiogenesis and ventricular function even 3 hours after the onset of ischemia, revealing a simple, clinically feasible approach to prevention of heart failure.Circulation Heart Failure 05/2011; 4(4):509-18. · 6.29 Impact Factor -
Article: Protease-resistant stromal cell-derived factor-1 for the treatment of experimental peripheral artery disease.
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ABSTRACT: Peripheral artery disease is a potentially incapacitating disease for which pharmacological options are limited. Stromal cell-derived 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. We 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. SDF-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.Circulation 03/2011; 123(12):1306-15. · 14.74 Impact Factor
