A free radical scavenger but not FGF-2-mediated angiogenic therapy rescues myonephropathic metabolic syndrome in severe hindlimb ischemia

• Published in: American journal of physiology. Heart and circulatory physiology 2006-04, Vol.290 (4), p.H1484-H1492
• Main Authors: Kaneko, Kazuhiro, Yonemitsu, Yoshikazu, Fujii, Takaaki, Onimaru, Mitsuho, Jin, Chen-Hao, Inoue, Makoto, Hasegawa, Mamoru, Onohara, Toshihiro, Maehara, Yoshihiko, Sueishi, Katsuo
• Format: Article
• Language: English
• Subjects: Angiogenesis Inducing Agents - administration & dosage; Animals; Antipyrine - administration & dosage; Antipyrine - analogs & derivatives; Fibroblast Growth Factor 2 - administration & dosage; Fibroblast Growth Factor 2 - genetics; Free Radical Scavengers - administration & dosage; Gene Transfer Techniques; Hindlimb - blood supply; Male; Metabolic Syndrome - drug therapy; Nephrosis - drug therapy; Nephrosis - therapy; Rats; Rats, Wistar; Reperfusion Injury - drug therapy; Rhabdomyolysis - drug therapy; Rhabdomyolysis - therapy; Severity of Illness Index; Treatment Outcome
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01006.2005

1 Division of Pathophysiological and Experimental Pathology, Department of Pathology, and 2 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka; and 3 DNAVEC Corporation, Tsukuba, Ibaraki, Japan Submitted 23 September 2005 ; accepted in final form 14 November 2005 The therapeutic use of angiogenic factors shows promise in the treatment of critical limb ischemia; however, its potential for myonephropathic 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 with 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 h, followed by 6 h of reperfusion. Administration of MCI-186 (twice; iv 5 min before induced ischemia and ip 5 min before reperfusion; 10 mg/kg, respectively), but not FGF-2 gene transfer (once, 48 h 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 (growth-related oncogene/cytokine-induced neutrophil chemoattractant-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. fibroblast growth factor-2; free radicals; critical limb ischemia; neutrophils Address for reprint requests and other correspondence: Y. Yonemitsu, Div. of Pathophysiological and Experimental Pathology, Dept. of Pathology, Graduate School of Medical Sciences, Kyushu Univ., 3–1-1 Maidashi, Higashi-ku, Fukuoka 812–8582, Japan (e-mail: yonemitu{at}pathol1.med.kyushu-u.ac.jp )