Inhibition of restenosis development after mechanical injury: a new field of application for malononitrilamides?
OBJECTIVE
To investigate the efficacy of the malononitrilamide FK778 to prevent vascular smooth muscle cell (SMC) migration/proliferation, and vascular fibrosis, the key events in restenosis development using in vivo and in vitro studies.


BACKGROUND
Since the high rate of restenosis after percutaneous transluminal coronary angioplasty limited its long-term success, the implementation of locally delivered antiproliferative/immunosuppressive agents became advantageous.


METHODS
Rats underwent balloon denudation of the abdominal aorta and received sirolimus, tacrolimus, or FK778 for 28 days in varying doses. Aortas were harvested for histologic evaluation, profibrotic gene expression, and organ chamber studies. Antifibrotic, antiproliferative and antimigratory effects of the immunosuppressants were further evaluated in vitro.


RESULTS
Histology of untreated animals revealed marked intimal hyperplasia with moderate luminal obliteration. Neointima formation was dose-dependently attenuated by all three agents with FK778 and sirolimus being most efficacious. Organ chamber relaxation studies showed a leftward shift of the nitroglycerin and the acetylcholine dose-responses in all treatment groups, indicating diminished endothelial dysfunction. In vivo, only FK778 treatment revealed a significant downregulation of the TGF-beta/vasorin system which could be explained by upregulation of the TGF-beta-inhibitory mediator SMAD7. In vitro, FK778 showed most potent antiproliferative and antimigratory effects on SMC compared with sirolimus and tacrolimus. Only the antiproliferative effect of FK778 was due to pyrimidine synthesis blockade and could be reversed by uridine supplementation.


CONCLUSIONS
The malononitrilamide FK778 proved highly efficacious against restenosis development by targeting two major components of intimal hyperplasia: SMC proliferation/migration and vascular fibrosis. Thus, the introduction of malononitrilamide-loaded stents may be a promising effort for future strategies.
Schrepfer
Sonja
S
Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany.
Deuse
Tobias
T
Sultan
Karim R
KR
Haddad
Munif
M
Böger
Rainer
R
Münzel
Thomas
T
Schäfer
Hansjörg
H
Pelletier
Marc P
MP
Robbins
Robert C
RC
Reichenspurner
Hermann
H
D000480:Alkynes / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects*; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control*; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D009570:Nitriles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000627:therapeutic use; D051906:Smad7 Protein / Q000378:metabolism; D016559:Tacrolimus / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000480:Alkynes; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D009570:Nitriles; D012333:RNA, Messenger; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D053773:Transforming Growth Factor beta1; D014665:Vasodilator Agents; C115284:2-cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)-2-hepten-6-ynamide; D020123:Sirolimus; D016559:Tacrolimus