C-type natriuretic peptide for reduction of restenosis: gene transfer is superior over single peptide administration

• Published in: The journal of gene medicine 2006-07, Vol.8 (7), p.835-844
• Main Authors: Pelisek, Jaroslav, Fuchs, Alexandra T., Kuehnl, Andreas, Tian, Wen, Kuhlmann, Michael T., Rolland, Pierre H., Mekkaoui, Choukri, Gaedtke, Lars, Nikol, Sigrid
• Format: Article
• Language: English
• Subjects: Angioplasty, Balloon - adverse effects; Animals; Base Sequence; C-type natriuretic peptide; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; Constriction, Pathologic; DNA - genetics; Endothelial Cells - cytology; Endothelial Cells - drug effects; endothelial repair; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Femoral Artery - drug effects; Femoral Artery - pathology; Gene Expression; Gene therapy; gene transfer; Gene Transfer Techniques; Liposomes; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Natriuretic Peptide, C-Type - administration & dosage; Natriuretic Peptide, C-Type - genetics; neointima formation; restenosis; Sus scrofa
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.905

Background Restenosis is still a significant clinical problem limiting the long‐term therapeutic success following balloon dilation or stent implantation. New approaches are necessary inhibiting neointima formation and simultaneously promoting re‐endothelialization. Therefore, long‐term therapeutic effects of adventitial liposome‐mediated C‐type natriuretic protein (CNP) gene and CNP peptide applications in a porcine model for restenosis post‐angioplasty were investigated. Methods For in vitro applications, primary cultures of porcine vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) were used. Gene transfer was performed with cationic lipid DOCSPER [1,3‐dioleoyloxy‐2‐(N5‐carbamoylspermine)propane]. In vivo treatment of pig femoral arteries was adventitial using a needle injection catheter following balloon angioplasty. Arteries were investigated by angiography, Evan's blue staining, histomorphometry, immunohistochemistry, PCR and RT‐PCR. Results Using CNP gene transfer in vitro, 29.4 ± 7.2% reduction of cell proliferation in VSMCs was observed. In ECs, the CNP gene did not compromise cellular growth. For the CNP peptide the optimal concentration was 1 mM with 50.7 ± 11.3% reduction of VSMC proliferation and 12.1 ± 5.3% enhancement of growth of ECs. Three weeks following application in vivo complete re‐endothelialization was observed in all treated groups. At 3 months significant reduction of neointima formation was observed using CNP gene vs. CNP peptide (85.9 ± 7.8% vs. 63.3 ± 27.6% reduction, P < 0.05) compared to control treatment. Conclusion Periadventitial liposome‐mediated CNP gene transfer in vivo resulted in a significant long‐term reduction of neointima formation without compromising endothelial repair and was superior over single CNP peptide administration. Advantages of CNP are its physiological origin and simultaneous inhibition of VSMC proliferation and promotion of EC growth. Copyright © 2006 John Wiley & Sons, Ltd.