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Arteriosclerosis, Thrombosis, and Vascular Biology
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on July 1, 2004

Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
Published online before print July 1, 2004, doi: 10.1161/01.ATV.0000137387.78515.61
A more recent version of this article appeared on September 1, 2004
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Submitted on May 4, 2004
Accepted on May 28, 2004

Functional Analysis of Genomic DNA, cDNA, and Nucleotide Sequence of the Mature C-Type Natriuretic Peptide Gene in Vascular Cells

Jaroslav Pelisek ; Andreas Kühnl ; Pierre H. Rolland ; Choukri Mekkaoui ; Alexandra Fuchs ; Greg F. Walker ; Manfred Ogris ; Ernst Wagner ; and Sigrid Nikol *

From the Department of Cardiology and Angiology (J.P., A.K., S.N.), University Hospital, Westfaelische Wilhelm University, Muenster, Germany; the Department of Pharmacy (J.P., G.F.W., M.O., E.W.), Center of Drug Research, Pharmaceutical Biology-Biotechnology; Paediatric Cardiology (A.F.), Klinikum Grosshadern, Ludwig Maximilian University, Munich, Germany; and Laboratoire Cardiovasculaire, Faculté de Médécine, Université de Marseille, France.

* To whom correspondence should be addressed. E-mail: nikol{at}uni-muenster.de.

Objective--The aim of this study was to investigate the effect of various C-type natriuretic peptide (CNP) sequences (genomic DNA [CNPDNA], cDNA derived from mRNA [CNPcDNA], and sequence coding for 22 amino acids of the mature CNP [CNP22aa]) on the growth of primary porcine vascular cells.

Methods and Results--Gene transfer was performed with cationic lipid DOCSPER or linear polyethylenimine. All 3 CNP sequences led to significant inhibition of smooth muscle cell (SMC) proliferation. In contrast, significant stimulation of cell growth was observed in endothelial cells (ECs) using CNPDNA or CNPcDNA but not CNP22aa. In a porcine restenosis model, a significant reduction in neointima hyperplasia was found 3 months after application of the CNPcDNA vector compared with the control transfection.

Conclusions--The results demonstrate that the first intron in the CNP sequence does not contain any additional enhancer-binding sites. However, the signal sequence is indispensable for secretion of CNP and its appropriate physiological function. Furthermore, the results show for the first time the therapeutic effect of CNP using liposome-mediated gene transfer and local adventitial delivery. Advantages of the CNP gene are its dual effects with inhibition of SMC proliferation and simultaneous promotion of EC growth.
Key words: C-type natriuretic peptide • vascular cells • gene transfer • proliferation • restenosis






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