Inhibitory Effects of Calcitonin Gene-Related Peptides on Experimental Vein Graft Disease

Abstract

Vein graft disease is a chronic inflammatory disease and limits the long-term clinical outcome of coronary revascularization. Because calcitonin gene-related peptide (CGRP) inhibits macrophage infiltration and inflammatory mediators, we hypothesized that transfected CGRP gene would inhibit macrophage infiltration and expression of inflammatory mediators in vein graft disease. Autologous rabbit jugular vein grafts were incubated ex vivo in a solution of mosaic adeno-associated virus vectors containing CGRP gene (AAV2/1.CGRP) or Escherichia coli B-galactosidase gene (LacZ) or a saline solution and then interposed in the carotid artery. Expression of CGRP gene was identified by reverse transcription-polymerase chain reaction, and E. coli LacZ gene expression was identified by X-gal staining. Intima to media ratios were evaluated at postoperative 4 weeks. Macrophages were identified with CD68 antibody by immunocytochemistry. Inflammatory mediators were measured with real-time polymerase chain reaction. The CGRP and LacZ gene expression were positive at postoperative 4 weeks. The intima to media ratio was significantly inhibited in the AAV2/1.CGRP group. Macrophage infiltration and expression of inflammatory mediators including monocyte chemoattractant protein-1, tumor necrosis factor-alpha, inducible nitric oxide synthase, and matrix metalloproteinase-9 were also significantly inhibited in the AAV2/1.CGRP group. Transfection of AAV2/1.CGRP inhibited inflammatory mediator expression, macrophage infiltration, and neointimal hyperplasia in experimental vein graft disease.