Published online before print February 25, 2002, doi: 10.1161/01.CIR.0000012146.07240.FD
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(Circulation. 2002;105:1491.)
© 2002 American Heart Association, Inc.
Impairment of Collateral Formation in Lipoprotein(a) Transgenic Mice
Therapeutic Angiogenesis Induced by Human Hepatocyte Growth Factor Gene
From the Division of Gene Therapy Science (R.M., M.S., S.I., Y.K.), the Department of Geriatric Medicine (R.M., K. Yamamoto, M.A., K. Yamasaki, T.O.), and the Division of Biochemistry, Department of Oncology, Biomedical Research Center (K.M., T.N.), Osaka University Medical School, Osaka, Japan; and CV Therapeutics (R.L.), Palo Alto, Calif.
Correspondence to Ryuichi Morishita, MD, PhD, Division of Gene Therapy Science, Osaka University Medical School, 2–2 Yamada-oka, Suita 565–0871, Japan. E-mail morishit{at}geriat.med.osaka-u.ac.jp
Background— Although lipoprotein(a) (Lp[a]) is a risk factor for atherosclerosis, no study has documented the effects of Lp(a) on angiogenesis. In this study, we examined collateral formation in peripheral arterial disease (PAD) model in Lp(a) transgenic mice. In addition, we examined the feasibility of gene therapy by using an angiogenic growth factor, hepatocyte growth factor (HGF), to treat PAD in the presence of high Lp(a).
Methods and Results— In Lp(a) transgenic mice, the degree of natural recovery of blood flow after operation was significantly lower than that in nontransgenic mice. Of importance, there was a significant negative correlation between serum Lp(a) concentration and the degree of natural recovery of blood flow (P<0.05). In addition, Lp(a) significantly stimulated the growth of vascular smooth muscle, accompanied by the phosphorylation of ERK. These data demonstrated the association of impairment of collateral formation with serum Lp(a) concentration. Thus, we examined the feasibility of therapeutic angiogenesis by using HGF, with the goal of progression to human gene therapy. Intramuscular injection of HGF plasmid resulted in a significant increase in blood flow even in Lp(a) transgenic mice, accompanied by the detection of human HGF protein. A significant increase in capillary density also was detected in Lp(a) transgenic mice transfected with human HGF compared with control (P<0.01).
Conclusions— Overall, a high serum Lp(a) concentration impaired collateral formation. Although the delay of angiogenesis in high serum Lp(a) might diminish angiogenesis, intramuscular injection of HGF plasmid induced therapeutic angiogenesis in the Lp(a) transgenic ischemic hindlimb mouse model as potential therapy for PAD.
Key Words: arteries • lipoproteins • angiogenesis • gene therapy • growth substances
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