Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers.
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-beta 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.
Hsieh
Patrick C H
PC
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Davis
Michael E
ME
Gannon
Joseph
J
MacGillivray
Catherine
C
Lee
Richard T
RT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006329:Heart Conduction System; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000166:cytology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats
D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin