Antisense Bcl-x oligonucleotide induces apoptosis and prevents arterial neointimal formation in murine cardiac allografts.
OBJECTIVE
Cardiac allograft arteriosclerosis, which limits long-term survival of recipients, cannot be prevented by conservative therapies. The arteriopathy is characterized by diffuse intimal thickening comprised of proliferative smooth muscle cells (SMCs). Cell death is a prominent feature of atherosclerosis; Bcl-x is one of the anti-apoptotic mediators.


METHODS
To test the hypothesis that antisense bcl-x oligodeoxynucleotide (ODN) is effective in preventing intimal hyperplasia through enhancing apoptosis after cardiac transplantation, we performed single intraluminal delivery of antisense bcl-x ODN into murine cardiac allografts (n = 9). DBA/2 (H-2d) hearts were transplanted into B10.D2 (H-2d) mice. Sense bcl-x ODN (n = 8) and no treatment (n = 8) studies were also performed.


RESULTS
Allografts were harvested at 4 weeks after transplantation; all allografts kept beating throughout the period. Coronary intimal thickening had developed in nontreated and sense ODN transfected allografts at 4 weeks after transplantation with enhanced expression of Bcl-x and cell adhesion molecules, and suppressed apoptosis. However, antisense bcl-x ODN prevented neointimal formation through enhanced apoptosis.


CONCLUSIONS
These results indicate that apoptosis of vascular SMCs induced by Bcl-x is associated with initial hyperplasia after heart transplantation. Antisense bcl-x ODN inhibits SMC proliferation by inducing apoptosis in graft coronary arteries.
Suzuki
J
J
Department of Internal Medicine I, Shinshu University School of Medicine, Nagano, Japan.
Isobe
M
M
Morishita
R
R
Nishikawa
T
T
Amano
J
J
Kaneda
Y
Y
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis; D001161:Arteriosclerosis / Q000517:prevention & control*; D003331:Coronary Vessels; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D016027:Heart Transplantation; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008081:Liposomes; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000235:genetics*; D018108:Respirovirus; D013873:Thionucleotides; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology*; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D013873:Thionucleotides; D051020:bcl-X Protein