Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers
Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers
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DOI：
10.1172/jci25878
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发表时间：
2006-01-01
影响因子：
15.9
通讯作者：
Lee, RT
中科院分区：
文献类型：
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作者：
Hsieh, PCH;Davis, ME;Lee, RT
内皮细胞可保护心肌细胞免受损伤，但其保护机制尚不完全清楚。在这里，我们证明了内皮细胞对心肌细胞的保护是通过PDGF-BB信号实现的。PDGF-BB以时间和剂量依赖的方式诱导心肌细胞Akt磷酸化，并通过PI3K/Akt信号通路抑制细胞凋亡。用可注射自组装肽纳米纤维在体外结合PDGF-BB，实现了PDGF-BB在注射部位的心肌持续给药14天。一项对96只大鼠的随机盲法研究表明，注射含有PDGF-BB的纳米纤维，但不注射纳米纤维或单独注射PDGF-BB，可以减少心肌细胞死亡，并保留心肌梗死后的收缩功能。一项对52只大鼠进行的单独的随机盲法研究表明，携带纳米纤维的PDGF-BB减少了缺血/再灌流后的脑梗塞范围。PDGF-BB复合纳米纤维可诱导心肌细胞PDGFR-P和Akt磷酸化。这些数据表明，内皮细胞通过PDGF-BB信号保护心肌细胞，这一体外发现可以转化为一种有效的在体保护心肌梗死后的方法。此外，这项研究表明，可注射的纳米纤维可以精确和持续地将蛋白质输送到心肌，具有潜在的治疗益处。
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-P 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.