Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers
Patrick C.H. Hsieh, … , Catherine MacGillivray, Richard T. Lee
Patrick C.H. Hsieh, … , Catherine MacGillivray, Richard T. Lee
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):237-248. https://doi.org/10.1172/JCI25878.
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Research Article Cardiology

Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers

Abstract

Endothelial cells can protect cardiomyocytes from injury, but the mechanism of this protection is incompletely described. Here we demonstrate that protection of cardiomyocytes by endothelial cells occurs through PDGF-BB signaling. PDGF-BB induced cardiomyocyte Akt phosphorylation in a time- and dose-dependent manner and prevented apoptosis via PI3K/Akt signaling. Using injectable self-assembling peptide nanofibers, which bound PDGF-BB in vitro, sustained delivery of PDGF-BB to the myocardium at the injected sites for 14 days was achieved. A blinded and randomized study in 96 rats showed that injecting nanofibers with PDGF-BB, but not nanofibers or PDGF-BB alone, decreased cardiomyocyte death and preserved systolic function after myocardial infarction. A separate blinded and randomized study in 52 rats showed that PDGF-BB delivered with nanofibers decreased infarct size after ischemia/reperfusion. PDGF-BB with nanofibers induced PDGFR-β and Akt phosphorylation in cardiomyocytes in vivo. These data demonstrate that endothelial cells protect cardiomyocytes via PDGF-BB signaling and that this in vitro finding can be translated into an effective in vivo method of protecting myocardium after infarction. Furthermore, this study shows that injectable nanofibers allow precise and sustained delivery of proteins to the myocardium with potential therapeutic benefits.

Authors

Patrick C.H. Hsieh, Michael E. Davis, Joseph Gannon, Catherine MacGillivray, Richard T. Lee

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Figure 9

Injection of NF/PDGF-BB does not increase myocardial angiogenesis/arteriogenesis, local blood flow, or inflammatory reaction after infarction.

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Injection of NF/PDGF-BB does not increase myocardial angiogenesis/arteri...
(A) Immunofluorescence staining of endothelial cells (isolectin, green) and VSMCs (α-SMA, red), counterstained with α-sarcomeric actinin and DAPI (blue) was used to evaluate capillaries and arteries, respectively, after 14 and 28 (data not shown) days of MI with or without injection of NF/PDGF-BB. Immunohistochemistry for macrophages (anti-mac3) and neutrophils (anti-neutrophil) was also performed to examine inflammatory reaction after 14 and 28 (data not shown) days of MI. Scale bars: 10 μm in endothelial cell stains, 20 μm in VSMC stains, and 5 μm in macrophage and neutrophil stains. Vascular and inflammatory cell densities were determined using fluorescence and light microscopy, and the results are shown in B (n ≥ 6 in each group; in total, ~200 capillaries, ~50 arteries, ~300 macrophages, and ~300 neutrophil cells counted in each animal). (C) A separate blinded and randomized study with 6 rats in each group was performed to measure local myocardial blood flow after 14 days of MI using fluorescent microspheres. No impact of PDGF-BB delivery on local blood flow was detected.