BACKGROUND: Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy. METHODS AND RESULTS: We devised a new strategy for anti-MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the human MCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E-knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content. CONCLUSIONS: We conclude that this anti-MCP-1 gene therapy may serve not only to reduce atherogenesis but also to stabilize vulnerable atheromatous plaques. This strategy may be a useful and feasible form of gene therapy against atherosclerosis in humans.
BACKGROUND: Monocyte recruitment into the arterial wall and its activation may be the central event in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is an important chemokine for monocyte recruitment, and its receptor (CCR2) may mediate such in vivo response. Although the importance of the MCP-1/CCR2 pathway in atherogenesis has been clarified, it remains unanswered whether postnatal blockade of the MCP-1 signals could be a unique site-specific gene therapy. METHODS AND RESULTS: We devised a new strategy for anti-MCP-1 gene therapy to treat atherosclerosis by transfecting an N-terminal deletion mutant of the humanMCP-1 gene into a remote organ (skeletal muscle) in apolipoprotein E-knockout mice. This strategy effectively blocked MCP-1 activity and inhibited the formation of atherosclerotic lesions but had no effect on serum lipid concentrations. Furthermore, this strategy increased the lesional extracellular matrix content. CONCLUSIONS: We conclude that this anti-MCP-1 gene therapy may serve not only to reduce atherogenesis but also to stabilize vulnerable atheromatous plaques. This strategy may be a useful and feasible form of gene therapy against atherosclerosis in humans.
Authors: Koichi Kozaki; Wolfgang E Kaminski; Jingjing Tang; Stan Hollenbach; Per Lindahl; Carol Sullivan; Jin-Chen Yu; Keith Abe; Paul J Martin; Russell Ross; Christer Betsholtz; Neill A Giese; Elaine W Raines Journal: Am J Pathol Date: 2002-10 Impact factor: 4.307
Authors: Zhenyu Yao; Michael Keeney; Tzu-Hua Lin; Jukka Pajarinen; Katherine Barcay; Heather Waters; Kensuke Egashira; Fan Yang; Stuart Goodman Journal: J Biomed Mater Res A Date: 2013-11-20 Impact factor: 4.396
Authors: Xinyi Jiang; Taishi Sato; Zhenyu Yao; Michael Keeney; Jukka Pajarinen; Tzu-Hua Lin; Florence Loi; Kensuke Egashira; Stuart Goodman; Fan Yang Journal: J Orthop Res Date: 2015-07-29 Impact factor: 3.494