Antimonocyte Chemoattractant Protein-1 Gene Therapy Attenuates Graft Vasculopathy

Abstract

Objective-Accelerated coronary arteriosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood, and there is no effective therapy. Transplant arteriosclerosis is characterized by early mononuclear cell attachment on the transplanted vessel followed by development of concentric neointimal hyperplasia. Early and persistent expression of monocyte chemoattractant protein-1 (MCP-1) in cardiac allografts has been implicated for the pathogenesis of transplant arteriosclerosis. Methods and Results-We investigated whether anti-MCP-1 gene therapy can inhibit the development of intima hyperplasia in a mouse model of cardiac transplantation. Either the dominant-negative form of MCP-1 (7ND) or control vector was transfected into the skeletal muscles of B10.D2 mice. Cardiac allografts from DBA/2 mice were transplanted heterotopically into B10.D2 mice. 7ND gene transfer was associated with a significant reduction of the number of mononuclear cells accumulating in the lumen of the graft coronary arteries at 1 week and an attenuation of the development of the lesion at 8 weeks (intima/media ratio 0.79Ϯ0.05 versus 0.48Ϯ0.04). Conclusions-The

Comprehensive analysis of inflammatory markers in chronic thromboembolic pulmonary hypertension patients

“…Also MCP-1, MlP1a and IL-6 were shown to promote migration of monocytes, macrophages and fibroblasts [26,27]. Furthermore, MCP-1-induced inflammation can lead to neointimal hyperplasia [28,29] and also stimulates fibroblast proliferation and collagen secretion [30]. Finally, in line with our observations, inflammatory cell infiltration was observed in the distal vascular end of the PEA material [8].…”

Anti–MCP-1 Gene Therapy Inhibits Vascular Smooth Muscle Cells Proliferation and Attenuates Vein Graft Thickening Both In Vitro and In Vivo

“…13,14,28 -30 Furthermore, in a mouse model of transplantation-induced graft vasculopathy after heterologous heart transplantation, 7ND MCP-1 overexpression significantly reduced accelerated atherosclerosis in the graft tissue. 31 However, the functional role of MCP-1 in the process of vein graft thickening, by intervening in the MCP-1/CCR2 pathway, was never studied. The data provided in this study demonstrate, to our knowledge for the first time, evidence for a pivotal, prorestenotic role of MCP-1 in vein graft disease.…”

Chemokines in Vascular Dysfunction and Remodeling

“…104 Although the mechanism of neointima reduction in vein grafts remains equivocal, monocyte recruitment and neointimal cell proliferation are significantly suppressed by inhibition of the MCP-1/ CCR2 axis 105 (Table 1). In CAV, MCP-1 is upregulated in arterioles 106,107 and infiltrating monocytes. 106 Gene transfer of 7ND reduces intimal hyperplasia and the recruitment of CCR2-positive macrophages into graft coronary arteries 107 ( Table 1).…”

“…In CAV, MCP-1 is upregulated in arterioles 106,107 and infiltrating monocytes. 106 Gene transfer of 7ND reduces intimal hyperplasia and the recruitment of CCR2-positive macrophages into graft coronary arteries 107 ( Table 1).…”