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Am J Physiol Heart Circ Physiol (June 20, 2002). doi:10.1152/ajpheart.00919.2001
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Articles in PresS, published online ahead of print June 20, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00919.2001
Submitted on November 1, 2001
Accepted on June 18, 2002

Anti-Monocyte Chemoattractant Protein-1 Gene Therapy Attenuates Pulmonary Hypertension in Rats

Yasuhiro Ikeda1, Yoshikazu Yonemitsu1*, Chu Kataoka2, Shiro Kitamoto2, Terutoshi Yamaoka3, Ken-ichi Nishida4, Akira Takeshita2, Kensuke Egashira2, and Katsuo Sueishi1

1 Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
2 Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
3 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
4 Tokyo R&D Center, Daiichi Pharmaceutical Co., Tokyo, Japan

* To whom correspondence should be addressed. E-mail: yonemitu{at}pathol1.med.kyushu-u.ac.jp.

Monocyte/macrophage chemoattractant protein-1 (MCP-1), a potent chemoattractant chemokine and an activator for mononuclear cells, may play a role in initiation and/or progression of pulmonary hypertension (PH). To determine if blockade of a systemic MCP-1 signal pathway in vivo may prevent PH, we intramuscularly transduced a naked plasmid encoding 7-N-terminus-deleted dominant negative inhibitor of MCP-1 (7ND MCP-1) gene in monocrotaline-induced PH. We also simultaneously gave a duplicate transfection at 2 week intervals or skeletal muscle-directed in vivo electroporation (EP) to evaluate if 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.







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