Anti-monocyte chemoattractant protein-1 gene therapy attenuates pulmonary hypertension in rats

被引:94
作者
Ikeda, Y
Yonemitsu, Y
Kataoka, C
Kitamoto, S
Yamaoka, T
Nishida, KI
Takeshita, A
Egashira, K
Sueishi, K
机构
[1] Kyushu Univ, Grad Sch Med Sci, Dept Pathol, Div Pathophysiol & Expt Pathol,Higashi Ku, Fukuoka 8128582, Japan
[2] Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka 8128582, Japan
[3] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka 8128582, Japan
[4] Daiichi Pharmaceut Co Ltd, Tokyo R&D Ctr, Tokyo 1038234, Japan
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2002年 / 283卷 / 05期
关键词
MCP-1; monocrotaline; electroporation;
D O I
10.1152/ajpheart.00919.2001
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Monocyte/macrophage chemoattractant protein-1 (MCP-1), a potent chemoattractant chemokine and an activator for mononuclear cells, may play a role in the initiation and/or progression of pulmonary hypertension (PH). To determine whether blockade of a systemic MCP-1 signal pathway in vivo may prevent PH, we intramuscularly transduced a naked plasmid encoding a 7-NH2 terminus-deleted dominant negative inhibitor of the MCP-1 (7ND MCP-1) gene in monocrotaline-induced PH. We also simultaneously gave a duplicate transfection at 2-wk intervals or skeletal muscle-directed in vivo electroporation (EP) to evaluate whether a longer or higher expression might be more effective. The intramuscular reporter gene expression was enhanced 10 times over that by EP than by simple injection, and a significant 7ND MCP-1 protein in plasma was detected only in the EP group. 7ND MCP-1 gene transfer significantly inhibited the progression of MCT-induced PH as evaluated by right ventricular systolic pressure, right ventricular hypertrophy, medial hypertrophy of pulumonary arterioles, and mononuclear cell infiltration into the lung. Differential effects of longer or higher transgene expression were not apparent. Although the in vivo kinetics of 7ND MCP-1 gene therapy should be studied further, these encouraging results suggest that an anti-inflammatory strategy via blockade of the MCP-1 signal pathway may be an alternative approach to treat subjects with PH.
引用
收藏
页码:H2021 / H2028
页数:8
相关论文
共 27 条
  • [1] Appetite-suppressant drugs and the risk of primary pulmonary hypertension
    Abenhaim, L
    Moride, Y
    Brenot, F
    Rich, S
    Benichou, J
    Kurz, X
    Higenbottam, T
    Oakley, C
    Wouters, E
    Aubier, M
    Simonneau, G
    Begaud, B
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1996, 335 (09) : 609 - 616
  • [2] Gene transfer into muscle by electroporation in vivo
    Aihara, H
    Miyazaki, J
    [J]. NATURE BIOTECHNOLOGY, 1998, 16 (09) : 867 - 870
  • [3] SURVIVAL IN PRIMARY PULMONARY-HYPERTENSION WITH LONG-TERM CONTINUOUS INTRAVENOUS PROSTACYCLIN
    BARST, RJ
    RUBIN, LJ
    MCGOON, MD
    CALDWELL, EJ
    LONG, WA
    LEVY, PS
    [J]. ANNALS OF INTERNAL MEDICINE, 1994, 121 (06) : 409 - 415
  • [4] PRIMARY PULMONARY-HYPERTENSION - A HISTOPATHOLOGIC STUDY OF 80 CASES
    BJORNSSON, J
    EDWARDS, WD
    [J]. MAYO CLINIC PROCEEDINGS, 1985, 60 (01) : 16 - 25
  • [5] BURKE AP, 1991, MODERN PATHOL, V4, P269
  • [6] Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor
    Cowan, KN
    Heilbut, A
    Humpl, T
    Lam, C
    Ito, S
    Rabinovitch, M
    [J]. NATURE MEDICINE, 2000, 6 (06) : 698 - 702
  • [7] Edwards W D, 1988, Cardiovasc Clin, V18, P321
  • [8] Anti-monocyte chemoattractant protein-1 gene therapy inhibits vascular remodeling in rats: blockade of MCP-1 activity after intramuscular transfer of a mutant gene inhibits vascular remodeling induced by chronic blockade of NO synthesis
    Egashira, K
    Koyanagi, M
    Kitamoto, S
    Ni, WH
    Kataoka, C
    Morishita, R
    Kaneda, Y
    Akiyama, C
    Nishida, KI
    Sueishi, K
    Takeshita, A
    [J]. FASEB JOURNAL, 2000, 14 (13) : 1974 - 1978
  • [9] Pulmonary hypertension
    Gaine, S
    [J]. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2000, 284 (24): : 3160 - 3168
  • [10] Hinderliter AL, 1997, CIRCULATION, V95, P1479