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

Abstract

Monocyte chemoattractant protein-1 (MCP-1) may play an essential part in the formation of arteriosclerosis by recruiting monocytes into the arterial wall. Thus, we devised a new strategy for anti-MCP-1 gene therapy against arteriosclerosis by transfecting an amino-terminal deletion mutant (missing the amino-terminal amino acids 2 to 8) of the human MCP-1 gene into a remote organ (skeletal muscles). Intramuscular transduction with the mutant MCP-1 gene blocked monocyte recruitment induced by a subcutaneous injection of recombinant MCP-1. In a rat model in which the chronic inhibition of endothelial nitric oxide synthesis induces early vascular inflammation as well as subsequent coronary vascular remodeling, this strategy suppressed monocyte recruitment into the coronary vessels and the development of vascular medial thickening, but did not reduce perivascular fibrosis. Thus, MCP-1 is necessary for the development of medial thickening but not for fibrosis in this model. This new strategy may be a useful and feasible gene therapy against arteriosclerosis.

A Monocyte Chemoattractant Protein-1 (MCP-1) Polymorphism And Outcome After Renal Transplantation

“…Just as with CCR1, CCR5, and CXCR3, specific blockade of MCP-1/ CCR2 interaction appears possible. In experimental atherosclerosis, another disease model that is modulated by MCP-1/ CCR2, overexpression of inactive MCP-1 resulted in significant inhibition of atherosclerotic lesion formation (27,28). Similar interventions might improve allograft survival.…”

Monocyte Chemoattractant Protein-1 Is an Essential Inflammatory Mediator in Angiotensin II-Induced Progression of Established Atherosclerosis in Hypercholesterolemic Mice

“…1 Recently, our group and others have also reported that MCP-1 has a vital role in the initiation and progression of atherosclerotic or arteriosclerotic lesions in experimental animals. [17][18][19][20][21][22][23][24] Essential roles of MCP-1 and its interactions with its receptor (CCR2) in AngII-induced arteriosclerosis are shown in CCR2-deficient mice. 25 Therefore, we hypothesized that AngII increases plaque size and promotes destabilization of established atherosclerotic lesions by activating MCP-1.…”

“…To block the MCP-1/CCR2 signal pathway, an N-terminal deletion mutant of the MCP-1 gene (7ND), which lacks the N-terminal amino acids 2 to 8, was transfected into the skeletal muscle. 17,18 This mutant MCP-1 binds to its receptor CCR2 and blocks MCP-1-mediated monocyte chemotaxis. In previous studies, we demonstrated that 7ND protein was secreted from the transfected skeletal muscle cells into the circulating blood and subsequently blocked MCP-1-induced chemotaxis in remote organs.…”

Anti—Monocyte Chemoattractant Protein-1 Gene Therapy Protects against Focal Brain Ischemia in Hypertensive Rats

“…We have recently reported that an N-terminal deletion mutant of human MCP-1 gene (7ND), which lacks the N-terminal amino acids 2 to 8, acts as a dominant nega-tive inhibitor for MCP-1 and blocks the MCP-1/CCR2 signal pathway in vivo (Egashira et al, 2000;Egashira, 2003). This mutant MCP-1 and normal MCP-1 form a heterodimer, which binds to the MCP-1 receptor (CCR-2) and completely inhibits MCP-1-mediated monocyte chemotaxis in vitro (Rollins, 1996).…”