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(Circulation. 2003;108:II-213.)
© 2003 American Heart Association, Inc.

Cardiac Transplantation and Surgery for Congestive Heart Failure

Transfection With a Dominant-Negative Inhibitor of Monocyte Chemoattractant Protein-1 Gene Improves Cardiac Function After 6 Hours of Cold Preservation

Noriyoshi Kajihara, MD; Shigeki Morita, MD; Takahiro Nishida, MD; Hideki Tatewaki, MD; Masataka Eto, MD; Kensuke Egashira, MD; Hisataka Yasui, MD

From the Department of Cardiovascular Surgery, and Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Correspondence to Shigeki Morita, MD, Department of Cardiovascular Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Phone: 81-92-642-5557; Fax: 81-92-642-5566; E-mail: morita{at}heart.med.kyushu-u.ac.jp

Background— Monocyte chemoattractant protein-1 (MCP-1), a potent chemotactic factor for monocytes, is induced during ischemia-reperfusion. As monocytes might play an important causative role in reperfusion injury, we investigated if inhibition of monocyte activation could attenuate ischemia-reperfusion injury and thereby improve cardiac preservation. To inhibit monocyte activation, we transfected a dominant-negative inhibitor of MCP-1 (7ND) gene in an animal model.

Methods and Results— We used an isolated rabbit heart preparation perfused with support-rabbit blood and transfected 7ND genes to skeletal muscle of the support rabbits (n=7) using electroporation technique; causing an elevation of serum 7ND level to 20±7 pg/mL at 5 days after transfection. Animals receiving empty plasmid served as controls (n=7). Five days after transfection, hearts from other rabbits were excised, stored in UW solution for 6hours, and perfused with blood from transfected support rabbits. The 7ND group showed better cardiac output (128.7±17.9 versus 81.6±19.8 mL/min; P<0.01), lower serum CK-MB levels (5.0±1.8 versus 11.1±2.9 ng/mL; P<0.01), lower serum IL-1ß levels (257.2±23.2 versus 311.2±37.4pg/mL; P<0.05), and lower serum TNF- levels (19.0±8.4 versus 35.1±13.0pg/mL; P<0.05). The numbers of infiltrating cells in myocardium were significantly reduced in the 7ND group.

Conclusions— Inhibition of MCP-1 with 7ND gene transfection reduced cytokine activation, attenuated myocardial damage, and improved cardiac function after 6 hours of preservation. These results show that MCP-1 plays an important role in ischemia-reperfusion injury.

Key Words: gene therapy • leukocytes • reperfusion injury • cytokines