Submitted on September 23, 2005
Accepted on November 14, 2005
A Free Radical Scavenger But Not FGF-2-mediated Angiogenic Therapy Rescues Myonephrophathic Metabolic Syndrome in Severe Hind Limb Ischemia
Kazuhiro Kaneko1, Yonemitsu2, Takaaki Fujii2, Mitsuho Onimaru2, Chen-Hao Jin2, Makoto Inoue3, Mamoru Hasegawa3, Toshihiro Onohara4, Yoshihiko Maehara4, and Katsuo Sueishi2*
1 Department of Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan; Department of Surgery and Science, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
2 Department of Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
3 DNAVEC Corporation, Tsukuba, Japan
4 Department of Surgery and Science, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
* To whom correspondence should be addressed. E-mail: yonemitu{at}pathol1.med.kyushu-u.ac.jp.
The therapeutic use of angiogenic factors shows promise in the treatment of critical limb ischemia; however, its potential for myonephrophathic metabolic syndrome (MNMS), a fatal complication caused by arterial reconstruction, has not been elucidated. The objective of this study was to evaluate the effectiveness of recombinant Sendai virus-mediated gene transfer of fibroblast growth factor-2 (FGF-2) directly compared to that of a radical scavenger, MCI-186, in a rat model of MNMS. MNMS was surgically induced by aortic occlusion below renal arteries for 4 hours, followed by 6 hours of reperfusion. Administration of MCI-186 (twice; i.v. 5 min before induced ischemia and i.p. 5 min before reperfusion, 10 mg/kg, respectively), but not FGF-2 gene transfer (once, 48 hours before induced ischemia), dramatically prevented the increase of serum biochemical markers as well as the edema of the gastrocnemius muscle. The effect of MCI-186 was accompanied by the marked suppression of the neutrophilic infiltration into the local (muscle) and remote (lung) organs. Although serum and muscular levels of a neutrophil-chemoattractant (GRO/CINC-1) were not affected by any treatment, the serum level of soluble intercellular adhesion molecule-1 was decreased by treatment with MCI-186 but not by treatment with FGF-2. These results suggest the distinct mechanism of MNMS from critical limb ischemia without reperfusion. Therefore, radical scavenging should be paid more attention than therapeutic angiogenesis when arterial circulation is reconstructed.
