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PRE-CLINICAL RESEARCH

Sustained Release of Erythropoietin Using Biodegradable Gelatin Hydrogel Microspheres Persistently Improves Lower Leg Ischemia

Longhu Li, MD^_*, Hideshi Okada, MD^_*, Genzou Takemura, MD^_*,_*, Masayasu Esaki, MD^_*, Hiroyuki Kobayashi, MD^_*, Hiromitsu Kanamori, MD^_*, Itta Kawamura, MD^_*, Rumi Maruyama, PhD^_*, Takako Fujiwara, MD, Hisayoshi Fujiwara, MD^_*, Yasuhiko Tabata, PhD and Shinya Minatoguchi, MD^_*

^_* Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan
Department of Food Science, Kyoto Women's University, Kyoto, Japan
Department of Biomaterials, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Manuscript received December 19, 2008; revised manuscript received February 18, 2009, accepted February 24, 2009.

^_* Reprint requests and correspondence: Dr. Genzou Takemura, Division of Cardiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan (Email: gt{at}cc.gifu-u.ac.jp).

Objectives: We hypothesized that erythropoietin (EPO)-immersed gelatin hydrogel microspheres (GHM) injected into ischemic legs might continuously release a small amount of EPO to locally stimulate angiogenesis without unfavorable systemic effects.

Background: EPO is a potent angiogenic factor, but its use for relieving ischemic organs is limited because of the untoward systemic erythrogenic effect and its short half-life in plasma.

Methods: The right femoral arteries of BALB/c mice were ligated. Recombinant human EPO (5,000 IU/kg)-immersed GHM was injected into the right hind limb muscles (n = 12); the control groups included a saline-injected group (n = 12), an EPO-injected group (n = 8), and an empty GHM-injected group (n = 8).

Results: Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the EPO-GHM group compared with any of the control groups. There was no increase in the hemoglobin level, nor was there any increase in endothelial progenitor cells. However, capillary and arteriolar densities were significantly increased in this group. Although the treatment did not affect the levels of vascular endothelial growth factor or interleukin-1 beta, it up-regulated the EPO receptor and matrix metalloproteinase-2 and activated the downstream signaling of Akt and also endothelial nitric oxide synthase in ischemic limbs, which might have been associated with the evident angiogenic and arteriogenic effects in the present system.

Conclusions: The present drug delivery system is suggested to have potential as a novel noninvasive therapy for ischemic peripheral artery disease.

Key Words: angiogenesis • erythropoietin • ischemia • vascular disease

Abbreviations and Acronyms   ASO = arteriosclerosis obliterans   eNOS = endothelial nitric oxide synthase   EPC = endothelial progenitor cell   EPO = erythropoietin   EPO-GHM = erythropoietin-immersed gelatin hydrogel microspheres   ERK = extracellular signal-regulated protein kinase   FACS = fluorescence-activated cell sorter   HPF = high-power field   STAT = signal transducer and activator of transcription   TUNEL = in situ nick end-labeling

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J. Am. Coll. Cardiol. 2009 53: A28. [Full Text] [PDF]