TY - JOUR
T1 - Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia
T2 - Benefits of a Novel Nonviral Vector, Gelatin
AU - Tokunaga, Noriyuki
AU - Nagaya, Noritoshi
AU - Shirai, Mikiyasu
AU - Tanaka, Etsuro
AU - Ishibashi-Ueda, Hatsue
AU - Harada-Shiba, Mariko
AU - Kanda, Munetake
AU - Ito, Takefumi
AU - Shimizu, Wataru
AU - Tabata, Yasuhiko
AU - Uematsu, Masaaki
AU - Nishigami, Kazuhiro
AU - Sano, Shunji
AU - Kangawa, Kenji
AU - Mori, Hidezo
PY - 2004/2/3
Y1 - 2004/2/3
N2 - Background-Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia. Methods and Results-Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ironically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60±0.02, 0.72±0.03, 0.42±0.06, respectively). Interestingly, hind limb perfusion and capillary density of ischemic muscles were highest in the AM-gelatin group, which revealed the highest content of AM in the muscles among the three groups. As a result, necrosis of lower hind limb and thigh muscles was minimal in the AM-gelatin group. Conclusions-AM gene transfer induced therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia. Furthermore, the use of biodegradable gelatin as a nonviral I vector augmented AM expression and thereby enhanced the therapeutic effects of AM gene transfer. Thus, gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of peripheral vascular diseases.
AB - Background-Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia. Methods and Results-Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ironically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60±0.02, 0.72±0.03, 0.42±0.06, respectively). Interestingly, hind limb perfusion and capillary density of ischemic muscles were highest in the AM-gelatin group, which revealed the highest content of AM in the muscles among the three groups. As a result, necrosis of lower hind limb and thigh muscles was minimal in the AM-gelatin group. Conclusions-AM gene transfer induced therapeutic angiogenesis in a rabbit model of chronic hind limb ischemia. Furthermore, the use of biodegradable gelatin as a nonviral I vector augmented AM expression and thereby enhanced the therapeutic effects of AM gene transfer. Thus, gelatin-mediated AM gene transfer may be a new therapeutic strategy for the treatment of peripheral vascular diseases.
KW - Angiogenesis
KW - Gene therapy
KW - Ischemia
KW - Peripheral vascular disease
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U2 - 10.1161/01.CIR.0000109700.81266.32
DO - 10.1161/01.CIR.0000109700.81266.32
M3 - Article
C2 - 14732745
AN - SCOPUS:10744219542
SN - 0009-7322
VL - 109
SP - 526
EP - 531
JO - Circulation
JF - Circulation
IS - 4
ER -
