LOCAL EXPRESSION OF C-TYPE NATRIURETIC PEPTIDE MARKEDLY SUPPRESSES NEOINTIMAL FORMATION IN RAT INJURED ARTERIES THROUGH AN AUTOCRINE PARACRINE LOOP/

Background In vivo gene transfer into injured arteries may provide a n ew means to facilitate molecular understanding of and to treat the int ractable fibroproliferative arterial diseases. Selection of an optimal molecule to be transferred will be a key to successful gene therapy i n the future. We tested the hypothesis that a secreted multifactorial molecule should act more efficiently through an autocrine/paracrine lo op to suppress neointimal formation elicited in injured arteries than a simple growth-inhibiting molecule that might be expressed inside cel ls. Methods and Results We constructed an adenoviral vector (AdCACNP) expressing C-type natriuretic peptide (CNP), a secreted stimulator of membrane-bound guanyl cyclase. AdCACNP directs cells to secrete large quantities of biologically active CNP. Serum-stimulated DNA synthesis and cell proliferation were only moderately suppressed in arterial smo oth muscle cells infected with AdCACNP in vitro. However, when AdCACNP was applied to balloon-injured rat carotid arteries in vivo, neointim al formation was markedly reduced (90% reduction) in an infection-site -specific manner without an increase in plasma CNP level. Conclusions Our results showed that CNP, a secreted multifactorial molecule, was i ndeed effective in suppressing fibroproliferative response in injured arteries and suggest that the potent antiproliferation effect may not be the most critical factor for the effective suppression of neointima l formation. An adenovirus-mediated expression of CNP could be an effe ctive and site-specific form of molecular intervention in proliferativ e arterial diseases.