on February 25, 2002
Published online before print February 25, 2002, doi: 10.1161/01.CIR.0000012146.07240.FD
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on December 6, 2001
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. * To whom correspondence should be addressed. 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.
Revised on January 15, 2002
Accepted on January 17, 2002
Impairment of Collateral Formation in
Lipoprotein(a) Transgenic Mice. Therapeutic Angiogenesis Induced by Human
Hepatocyte Growth Factor Gene
Ryuichi Morishita MD, PhD*,
Key words: arteries • lipoproteins • angiogenesis • gene therapy • growth substances
This article has been cited by other articles:
 |
|
 |
|
  T. Kinnaird, E. Stabile, S. Zbinden, M.-S. Burnett, and S. E. Epstein Cardiovascular risk factors impair native collateral development and may impair efficacy of therapeutic interventions Cardiovasc Res, May 1, 2008; 78(2): 257 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Cai, B. H. Johnstone, T. G. Cook, Z. Liang, D. Traktuev, K. Cornetta, D. A. Ingram, E. D. Rosen, and K. L. March Suppression of Hepatocyte Growth Factor Production Impairs the Ability of Adipose-Derived Stem Cells to Promote Ischemic Tissue Revascularization Stem Cells, December 1, 2007; 25(12): 3234 - 3243. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Morishita, M. Aoki, and T. Ogihara Does gene therapy become pharmacotherapy? Exp Physiol, May 1, 2005; 90(3): 307 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Coats and R. Wadsworth Marriage of resistance and conduit arteries breeds critical limb ischemia Am J Physiol Heart Circ Physiol, March 1, 2005; 288(3): H1044 - H1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Arenillas, J. Alvarez-Sabin, J. Montaner, A. Rosell, C. A. Molina, A. Rovira, M. Ribo, E. Sanchez, and M. Quintana Angiogenesis in Symptomatic Intracranial Atherosclerosis: Predominance of the Inhibitor Endostatin Is Related to a Greater Extent and Risk of Recurrence Stroke, January 1, 2005; 36(1): 92 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nanba, S. Kuroda, T. Ishikawa, K. Houkin, and Y. Iwasaki Increased Expression of Hepatocyte Growth Factor in Cerebrospinal Fluid and Intracranial Artery in Moyamoya Disease Stroke, December 1, 2004; 35(12): 2837 - 2842. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Morishita, M. Aoki, N. Hashiya, H. Makino, K. Yamasaki, J. Azuma, Y. Sawa, H. Matsuda, Y. Kaneda, and T. Ogihara Safety Evaluation of Clinical Gene Therapy Using Hepatocyte Growth Factor to Treat Peripheral Arterial Disease Hypertension, August 1, 2004; 44(2): 203 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hashiya, N. Jo, M. Aoki, K. Matsumoto, T. Nakamura, Y. Sato, N. Ogata, T. Ogihara, Y. Kaneda, and R. Morishita In Vivo Evidence of Angiogenesis Induced by Transcription Factor Ets-1: Ets-1 Is Located Upstream of Angiogenesis Cascade Circulation, June 22, 2004; 109(24): 3035 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hisaka, M. Ieda, T. Nakamura, K.-i. Kosai, S. Ogawa, and K. Fukuda Powerful and controllable angiogenesis by using gene-modified cells expressing human hepatocyte growth factor and thymidine kinase J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1915 - 1922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hiraoka, H. Koike, S. Yamamoto, N. Tomita, C. Yokoyama, T. Tanabe, T. Aikou, T. Ogihara, Y. Kaneda, and R. Morishita Enhanced Therapeutic Angiogenesis by Cotransfection of Prostacyclin Synthase Gene or Optimization of Intramuscular Injection of Naked Plasmid DNA Circulation, November 25, 2003; 108(21): 2689 - 2696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rehman, R. V. Considine, J. E. Bovenkerk, J. Li, C. A. Slavens, R. M. Jones, and K. L. March Obesity is associated with increased levels of circulating hepatocyte growth factor J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1408 - 1413. [Abstract] [Full Text] [PDF]
|
|