Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide.
Endothelium-derived relaxing factor is important for vascular homeostasis and possesses qualities that may modulate vascular injury, including vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation. S-nitrososerum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a potent vasodilator and platelet inhibitor. Given the avidity of serum albumin for subendothelial matrix and the antiproliferative effects of NO, we investigated the effects of locally delivered S-nitroso-bovine serum albumin (S-NO-BSA) and a polythiolated form of bovine serum albumin (pS-BSA) modified to carry several S-nitrosothiol groups (pS-NO-BSA) on neointimal responses in an animal model of vascular injury. Locally delivered S-NO-BSA bound preferentially to denuded rabbit femoral vessels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029). pS-NO-BSA significantly reduced the intimal/medial ratio (P = 0.038) and did so in conjunction with elevations in platelet (P < 0.001) and vascular cGMP content (P < or = 0.001). pS-NO-BSA treatment also inhibited platelet deposition (P = 0.031) after denuding injury. Comparison of BSA, S-NO-BSA, pS-NO-BSA, and control revealed a dose-response relationship between the amount of displaceable NO delivered and the extent of inhibition of neointimal proliferation at 2 wk (P < or = 0.001). Local administration of a stable protein S-nitrosothiol inhibits intimal proliferation and platelet deposition after vascular arterial balloon injury. This strategy for the local delivery of a long-lived NO adduct has potential for preventing restenosis after angioplasty.
Marks
D S
DS
Department of Medicine, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Vita
J A
JA
Folts
J D
JD
Keaney
J F
JF
Welch
G N
GN
Loscalzo
J
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007205:Indium Radioisotopes; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology*; D009603:Nitroso Compounds; D010973:Platelet Adhesiveness / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects / Q000473:pathology*
D007205:Indium Radioisotopes; D009603:Nitroso Compounds; C091665:S-nitrosoalbumin; D013438:Sulfhydryl Compounds; D012710:Serum Albumin, Bovine; D009569:Nitric Oxide; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine